2018 |
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Baillie, J. K.; Bretherick, A.; Haley, C. S.; Clohisey, S.; Gray, A.; Neyton, L. P. A.; Barrett, J.; Stahl, E. A.; Tenesa, A.; Andersson, R.; Brown, J. B.; Faulkner, G. J.; Lizio, M.; Schaefer, U.; Daub, C.; Itoh, M.; Kondo, N.; Lassmann, T.; Kawai, J.; Mole, D.; Bajic, V. B.; Heutink, P.; Rehli, M.; Kawaji, H.; Sandelin, A.; Suzuki, H.; Satsangi, J.; Wells, C. A.; Hacohen, N.; Freeman, T. C.; Hayashizaki, Y.; Carninci, P.; Forrest, A. R. R.; Hume, D. A.; Consortium, IIBDGC Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease (Journal Article) In: PLoS Computational Biology, vol. 14, no. 3, 2018, ISSN: 1553734X, (Publisher: Public Library of Science). @article{baillie_shared_2018,Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn’s disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits. © 2018 Baillie et al. | |
Pridans, C.; Sauter, K. A.; Irvine, K. M.; Davis, G. M.; Lefevre, L.; Raper, A.; Rojo, R.; Nirmal, A. J.; Beard, P.; Cheeseman, M.; Hume, D. A. Macrophage colony-stimulating factor increases hepatic macrophage content, liver growth, and lipid accumulation in neonatal rats (Journal Article) In: American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 314, no. 3, pp. G388–G398, 2018, ISSN: 01931857, (Publisher: American Physiological Society). @article{pridans_macrophage_2018,Signaling via the colony-stimulating factor 1 receptor (CSF1R) controls the survival, differentiation, and proliferation of macrophages. Mutations in CSF1 or CSF1R in mice and rats have pleiotropic effects on postnatal somatic growth. We tested the possible application of pig CSF1-Fc fusion protein as a therapy for low birth weight (LBW) at term, using a model based on maternal dexamethasone treatment in rats. Neonatal CSF1-Fc treatment did not alter somatic growth and did not increase the blood monocyte count. Instead, there was a substantial increase in the size of liver in both control and LBW rats, and the treatment greatly exacerbated lipid droplet accumulation seen in the dexamethasone LBW model. These effects were reversed upon cessation of treatment. Transcriptional profiling of the livers supported histochemical evidence of a large increase in macrophages with a resident Kupffer cell phenotype and revealed increased expression of many genes implicated in lipid droplet formation. There was no further increase in hepatocyte proliferation over the already high rates in neonatal liver. In conclusion, treatment of neonatal rats with CSF1-Fc caused an increase in liver size and hepatic lipid accumulation, due to Kupffer cell expansion and/or activation rather than hepatocyte proliferation. Increased liver macrophage numbers and expression of endocytic receptors could mitigate defective clearance functions in neonates. NEW & NOTEWORTHY This study is based on extensive studies in mice and pigs of the role of CSF1/CSF1R in macrophage development and postnatal growth. We extended the study to neonatal rats as a possible therapy for low birth weight. Unlike our previous studies in mice and pigs, there was no increase in hepatocyte proliferation and no increase in monocyte numbers. Instead, neonatal rats treated with CSF1 displayed reversible hepatic steatosis and Kupffer cell expansion. © 2018 American Physiological Society. | |
Hume, D.; Stulemeijer, T. The centraliser lattice (Book) Cambridge University Press, 2018, ISBN: 978-1-108-33267-5 978-1-108-41312-1, (Publication Title: New Directions in Locally Compact Groups). @book{hume_centraliser_2018,In this chapter, we review the definition of the centraliser lattice C(G) of a totally disconnected locally compact (tdlc) group, and explain why it is a Boolean algebra. We then study the action of G on Ω, the associated Stone space of C(G), and prove that under certain hypotheses on G, the action is continuous, minimal, strongly proximal and micro-supported. Moreover, Ω satisfies a universal property in the category of profinite G-spaces that are micro-supported. © Cambridge University Press 2018. All rights reserved. | |
Leday, G. G. R.; Vértes, P. E.; Richardson, S.; Greene, J. R.; Regan, T.; Khan, S.; Henderson, R.; Freeman, T. C.; Pariante, C. M.; Harrison, N. A.; Vertes, P.; Cardinal, R.; Richardson, S.; Leday, G.; Freeman, T.; Regan, T.; Hume, D.; Wu, Z.; Cattaneo, A.; Zunszain, P.; Borsini, A.; Stewart, R.; Chandran, D.; Carvalho, L.; Bell, J.; Souza-Teodoro, L.; Perry, H.; Harrison, N.; Drevets, W.; Wittenberg, G.; Jones, D.; Khan, S.; Stylianou, A.; Henderson, R.; Perry, V. H.; Drevets, W. C.; Wittenberg, G. M.; Bullmore, E. T.; Consortium, MRC Immunopsychiatry Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder (Journal Article) In: Biological Psychiatry, vol. 83, no. 1, pp. 70–80, 2018, ISSN: 00063223, (Publisher: Elsevier USA). @article{leday_replicable_2018,Background Peripheral inflammation is often associated with major depressive disorder (MDD), and immunological biomarkers of depression remain a focus of investigation. Methods We used microarray data on whole blood from two independent case-control studies of MDD: the GlaxoSmithKline–High-Throughput Disease-specific target Identification Program [GSK-HiTDiP] study (113 patients and 57 healthy control subjects) and the Janssen–Brain Resource Company study (94 patients and 100 control subjects). Genome-wide differential gene expression analysis (18,863 probes) resulted in a p value for each gene in each study. A Bayesian method identified the largest p-value threshold (q =.025) associated with twice the number of genes differentially expressed in both studies compared with the number of coincidental case-control differences expected by chance. Results A total of 165 genes were differentially expressed in both studies with concordant direction of fold change. The 90 genes overexpressed (or UP genes) in MDD were significantly enriched for immune response to infection, were concentrated in a module of the gene coexpression network associated with innate immunity, and included clusters of genes with correlated expression in monocytes, monocyte-derived dendritic cells, and neutrophils. In contrast, the 75 genes underexpressed (or DOWN genes) in MDD were associated with the adaptive immune response and included clusters of genes with correlated expression in T cells, natural killer cells, and erythroblasts. Consistently, the MDD patients with overexpression of UP genes also had underexpression of DOWN genes (correlation textgreater.70 in both studies). Conclusions MDD was replicably associated with proinflammatory activation of the peripheral innate immune system, coupled with relative inactivation of the adaptive immune system, indicating the potential of transcriptional biomarkers for immunological stratification of patients with depression. © 2017 Society of Biological Psychiatry | |
2017 |
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Sehgal, Anuj; Kobayashi, Atsushi; Donaldson, David S.; Mabbott, Neil A. c-Rel is dispensable for the differentiation and functional maturation of M cells in the follicle-associated epithelium (Journal Article) In: Immunobiology, vol. 222, no. 2, pp. 316–326, 2017, ISSN: 01712985. @article{sehgal_c-rel_2017, | |
Jubb, A. W.; Boyle, S.; Hume, D. A.; Bickmore, W. A. Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci (Journal Article) In: Cell Reports, vol. 21, no. 11, pp. 3022–3031, 2017, ISSN: 22111247, (Publisher: Elsevier B.V.). @article{jubb_glucocorticoid_2017,Glucocorticoids act by binding to the glucocorticoid receptor (GR), which binds to specific motifs within enhancers of target genes to activate transcription. Previous studies have suggested that GRs can promote interactions between gene promoters and distal elements within target loci. In contrast, we demonstrate here that glucocorticoid addition to mouse bone-marrow-derived macrophages produces very rapid chromatin unfolding detectable by fluorescence in situ hybridization (FISH) at loci associated with GR binding. Rapid chromatin decompaction was generally not dependent on transcription at those loci that are known to be inducible in both mouse and human macrophages and was sustained for up to 5 days following ligand removal. Chromatin decompaction was not dependent upon persistent GR binding, which decayed fully after 24 hr. We suggest that sustained large-scale chromatin reorganization forms an important part of the response to glucocorticoid and might contribute to glucocorticoid sensitivity and resistance. Glucocorticoids are important anti-inflammatory therapeutics. Jubb at al. find that treating primary macrophages with glucocorticoid induces rapid and persistent chromatin reorganization at genes that respond in both mice and humans. Higher-order chromatin structure at these core loci may be involved in the glucocorticoid response and be relevant to resistance. © 2017 The Author(s) | |
Hume, D. A.; Wollscheid-Lengeling, E.; Rojo, R.; Pridans, C. The evolution of the macrophage-specific enhancer (Fms intronic regulatory element) within the CSF1R locus of vertebrates (Journal Article) In: Scientific Reports, vol. 7, no. 1, 2017, ISSN: 20452322, (Publisher: Nature Publishing Group). @article{hume_evolution_2017,The Csf1r locus encodes the receptor for macrophage colony-stimulating factor, which controls the proliferation, differentiation and survival of macrophages. The 300 bp Fms intronic regulatory element (FIRE), within the second intron of Csf1r, is necessary and sufficient to direct macrophage-specific transcription. We have analysed the conservation and divergence of the FIRE DNA sequence in vertebrates. FIRE is present in the same location in the Csf1r locus in reptile, avian and mammalian genomes. Nearest neighbor analysis based upon this element alone largely recapitulates phylogenies inferred from much larger genomic sequence datasets. One core element, containing binding sites for AP1 family and the macrophage-specific transcription factor, PU.1, is conserved from lizards to humans. Around this element, the FIRE sequence is conserved within clades with the most conserved elements containing motifs for known myeloid-expressed transcription factors. Conversely, there is little alignment between clades outside the AP1/PU.1 element. The analysis favours a hybrid between "enhanceosome" and "smorgasbord" models of enhancer function, in which elements cooperate to bind components of the available transcription factor milieu. © 2017 The Author(s). | |
Farro, G.; Stakenborg, M.; Gomez-Pinilla, P. J.; Labeeuw, E.; Goverse, G.; Giovangiulio, M. D.; Stakenborg, N.; Meroni, E.; D'Errico, F.; Elkrim, Y.; Laoui, D.; Lisowski, Z. M.; Sauter, K. A.; Hume, D. A.; Ginderachter, J. A. Van; Boeckxstaens, G. E.; Matteoli, G. CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus (Journal Article) In: Gut, vol. 66, no. 12, pp. 2098–2109, 2017, ISSN: 00175749, (Publisher: BMJ Publishing Group). @article{farro_ccr2-dependent_2017,Objective Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility. Design IM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, Ccr2 -/ - mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (Mφs) during onset and resolution of ME inflammation. Results At early time points, IM-induced GI transit delay and inflammation were equal in WT and Ccr2 - / - mice. However, GI transit recovery after IM was significantly delayed in Ccr2 - / - mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived Mφs acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with Mφ colony-stimulating factor 1 enhanced monocyte recruitment and Mφ differentiation and ameliorated GI transit in Ccr2 - / - mice. Conclusion Our study reveals a critical role for monocyte-derived Mφs in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing Mφ physiological repair functions. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. | |
Hume, D.; Sisto, A. Groups with no coarse embeddings into hyperbolic groups (Journal Article) In: New York Journal of Mathematics, vol. 23, pp. 1657–1670, 2017, ISSN: 10769803, (Publisher: University at Albany). @article{hume_groups_2017,We introduce an obstruction to the existence of a coarse embedding of a given group or space into a hyperbolic group, or more generally into a hyperbolic graph of bounded degree. The condition we consider is “admitting exponentially many fat bigons”, and it is preserved by a coarse embedding between graphs with bounded degree. Groups with exponential growth and linear divergence (such as direct products of two groups one of which has exponential growth, solvable groups that are not virtually nilpotent, and uniform higher-rank lattices) have this property and hyperbolic graphs do not, so the former cannot be coarsely embedded into the latter. Other examples include certain lacunary hyperbolic and certain small cancellation groups. © 2017, University at Albany. All rights reserved. | |
Summers, K. M.; Hume, D. A. Identification of the macrophage-specific promoter signature in FANTOM5 mouse embryo developmental time course data (Journal Article) In: Journal of Leukocyte Biology, vol. 102, no. 4, pp. 1081–1092, 2017, ISSN: 07415400, (Publisher: Federation of American Societies for Experimental Biology). @article{summers_identification_2017,The FANTOM5 consortium used cap analysis of gene expression (CAGE) to analyze the time course of gene expression over development from 11 days postcoitum (dpc) to adult in 16 developing organs and the whole body of the mouse. Every tissue in the body contains a large number of resident macrophages that initially infiltrate the embryo from the yolk sac. These cells contribute to organogenesis, and their functions diversify during development as they acquire tissue-specific adaptations. In each of the FANTOM5 time courses, the expression of known macrophage-specific genes, including CSF1 receptor (Csf1r), epidermal growth factorlike module-containing mucin-like hormone receptor-like 1 (Emr1), and mer receptor tyrosine kinase (Mertk), was readily detectable and increased with time. We reasoned that genes expressed by macrophages would be strongly correlated in their expression with these known markers and might vary between tissues. We used the network analysis tool, Miru, to extract the sets of coexpressed genes from the time course and identified a core set of coexpressed genes attributable to embryonic macrophages, including some, such as dehydrogenase/reductase 3 (Dhrs3), that may have unique functions in development. The FANTOM5 data also detected the appearance of tissue-specific macrophage-expressed genes, such as T cell Ig and mucin domain-containing 4 (Timd4) and V-set and Ig domain-containing 4 (Vsig4) in liver and sialic acid-binding Ig-like lectin 5 (Siglec5) in lung, and confirmed that macrophage content increases with time in each organ as the proliferative phases end, and tissue-specific gene-expression increases. The FANTOM5 data are available on a comprehensive browser (http://fantom.gsc.riken.jp/zenbu/), which provides a resource for the study of macrophage transcriptional regulation and roles in mouse development. © Society for Leukocyte Biology. | |
Clark, E. L.; Bush, S. J.; McCulloch, M. E. B.; Farquhar, I. L.; Young, R.; Lefevre, L.; Pridans, C.; Tsang, H.; Wu, C.; Afrasiabi, C.; Watson, M.; Whitelaw, C. B.; Freeman, T. C.; Summers, K. M.; Archibald, A. L.; Hume, D. A. A high resolution atlas of gene expression in the domestic sheep (Ovis aries) (Journal Article) In: PLoS Genetics, vol. 13, no. 9, 2017, ISSN: 15537390, (Publisher: Public Library of Science). @article{clark_high_2017,Sheep are a key source of meat, milk and fibre for the global livestock sector, and an important biomedical model. Global analysis of gene expression across multiple tissues has aided genome annotation and supported functional annotation of mammalian genes. We present a large-scale RNA-Seq dataset representing all the major organ systems from adult sheep and from several juvenile, neonatal and prenatal developmental time points. The Ovis aries reference genome (Oar v3.1) includes 27,504 genes (20,921 protein coding), of which 25,350 (19,921 protein coding) had detectable expression in at least one tissue in the sheep gene expression atlas dataset. Network-based cluster analysis of this dataset grouped genes according to their expression pattern. The principle of ‘guilt by association’ was used to infer the function of uncharacterised genes from their co-expression with genes of known function. We describe the overall transcriptional signatures present in the sheep gene expression atlas and assign those signatures, where possible, to specific cell populations or pathways. The findings are related to innate immunity by focusing on clusters with an immune signature, and to the advantages of cross-breeding by examining the patterns of genes exhibiting the greatest expression differences between purebred and crossbred animals. This high-resolution gene expression atlas for sheep is, to our knowledge, the largest transcriptomic dataset from any livestock species to date. It provides a resource to improve the annotation of the current reference genome for sheep, presenting a model transcriptome for ruminants and insight into gene, cell and tissue function at multiple developmental stages. © 2017 Clark et al. | |
Macdonald, S. E.; Nolan, M. J.; Harman, K.; Boulton, K.; Hume, D. A.; Tomley, F. M.; Stabler, R. A.; Blake, D. P. Effects of Eimeria tenella infection on chicken caecal microbiome diversity, exploring variation associated with severity of pathology (Journal Article) In: PLoS ONE, vol. 12, no. 9, 2017, ISSN: 19326203, (Publisher: Public Library of Science). @article{macdonald_effects_2017,Eimeria species cause the intestinal disease coccidiosis, most notably in poultry. While the direct impact of coccidiosis on animal health and welfare is clear, its influence on the enteric microbiota and by-stander effects on chicken health and production remains largely unknown, with the possible exception of Clostridium perfringens (necrotic enteritis). This study evaluated the composition and structure of the caecal microbiome in the presence or absence of a defined Eimeria tenella challenge infection in Cobb500 broiler chickens using 16S rRNA amplicon sequencing. The severity of clinical coccidiosis in individual chickens was quantified by caecal lesion scoring and microbial changes associated with different lesion scores identified. Following E. tenella infection the diversity of taxa within the caecal microbiome remained largely stable. However, infection induced significant changes in the abundance of some microbial taxa. The greatest changes were detected in birds displaying severe caecal pathology; taxa belonging to the order Enterobacteriaceae were increased, while taxa from Bacillales and Lactobacillales were decreased with the changes correlated with lesion severity. Significantly different profiles were also detected in infected birds which remained asymptomatic (lesion score 0), with taxa belonging to the genera Bacteroides decreased and Lactobacillus increased. Many differential taxa from the order Clostridiales were identified, with some increasing and others decreasing in abundance in Eimeria-infected animals. The results support the view that caecal microbiome dysbiosis associated with Eimeria infection contributes to disease pathology, and could be a target for intervention to mitigate the impact of coccidiosis on poultry productivity and welfare. This work highlights that E. tenella infection has a significant impact on the abundance of some caecal bacteria with notable differences detected between lesion score categories emphasising the importance of accounting for differences in caecal lesions when investigating the relationship between E. tenella and the poultry intestinal microbiome. © 2017 Macdonald et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |
Noguchi, S.; Arakawa, T.; Fukuda, S.; Furuno, M.; Hasegawa, A.; Hori, F.; Ishikawa-Kato, S.; Kaida, K.; Kaiho, A.; Kanamori-Katayama, M.; Kawashima, T.; Kojima, M.; Kubosaki, A.; Manabe, R. -I.; Murata, M.; Nagao-Sato, S.; Nakazato, K.; Ninomiya, N.; Nishiyori-Sueki, H.; Noma, S.; Saijyo, E.; Saka, A.; Sakai, M.; Simon, C.; Suzuki, N.; Tagami, M.; Watanabe, S.; Yoshida, S.; Arner, P.; Axton, R. A.; Babina, M.; Baillie, J. Kenneth; Barnett, T. C.; Beckhouse, A. G.; Blumenthal, A.; Bodega, B.; Bonetti, A.; Briggs, J.; Brombacher, F.; Carlisle, A. J.; Clevers, H. C.; Davis, C. A.; Detmar, M.; Dohi, T.; Edge, B. A. S.; Edinger, M.; Ehrlund, A.; Ekwall, K.; Endoh, M.; Enomoto, H.; Eslami, A.; Fagiolini, M.; Fairbairn, L.; Farach-Carson, M. C.; Faulkner, G. J.; Ferrai, C.; Fisher, M. E.; Forrester, L. M.; Fujita, R.; Furusawa, J. -I.; Geijtenbeek, T. B.; Gingeras, T.; Goldowitz, D.; Guhl, S.; Guler, R.; Gustincich, S.; Ha, T. J.; Hamaguchi, M.; Hara, M.; Hasegawa, Y.; Herlyn, M.; Heutink, P.; Hitchens, K. J.; Hume, D. A.; Ikawa, T.; Ishizu, Y.; Kai, C.; Kawamoto, H.; Kawamura, Y. I.; Kempfle, J. S.; Kenna, T. J.; Kere, J.; Khachigian, L. M.; Kitamura, T.; Klein, S.; Klinken, S. Peter; Knox, A. J.; Kojima, S.; Koseki, H.; Koyasu, S.; Lee, W.; Lennartsson, A.; MacKay-Sim, A.; Mejhert, N.; Mizuno, Y.; Morikawa, H.; Morimoto, M.; Moro, K.; Morris, K. J.; Motohashi, H.; Mummery, C. L.; Nakachi, Y.; Nakahara, F.; Nakamura, T.; Nakamura, Y.; Nozaki, T.; Ogishima, S.; Ohkura, N.; Ohno, H.; Ohshima, M.; Okada-Hatakeyama, M.; Okazaki, Y.; Orlando, V.; Ovchinnikov, D. A.; Passier, R.; Patrikakis, M.; Pombo, A.; Pradhan-Bhatt, S.; Qin, X. -Y.; Rehli, M.; Rizzu, P.; Roy, S.; Sajantila, A.; Sakaguchi, S.; Sato, H.; Satoh, H.; Savvi, S.; Saxena, A.; Schmidl, C.; Schneider, C.; Schulze-Tanzil, G. G.; Schwegmann, A.; Sheng, G.; Shin, J. W.; Sugiyama, D.; Sugiyama, T.; Summers, K. M.; Takahashi, N.; Takai, J.; Tanaka, H.; Tatsukawa, H.; Tomoiu, A.; Toyoda, H.; Wetering, M.; Berg, L. M. V. D.; Verardo, R.; Vijayan, D.; Wells, C. A.; Winteringham, L. N.; Wolvetang, E.; Yamaguchi, Y.; Yamamoto, M.; Yanagi-Mizuochi, C.; Yoneda, M.; Yonekura, Y.; Zhang, P. G.; Zucchelli, S.; Abugessaisa, I.; Arner, E.; Harshbarger, J.; Kondo, A.; Lassmann, T.; Lizio, M.; Sahin, S.; Sengstag, T.; Severin, J.; Shimoji, H.; Suzuki, M.; Suzuki, H.; Kawai, J.; Kondo, N.; Itoh, M.; Daub, C. O.; Kasukawa, T.; Kawaji, H.; Carninci, P.; Forrest, A. R. R.; Hayashizaki, Y. FANTOM5 CAGE profiles of human and mouse samples (Journal Article) In: Scientific Data, vol. 4, 2017, ISSN: 20524463, (Publisher: Nature Publishing Groups). @article{noguchi_fantom5_2017,In the FANTOM5 project, transcription initiation events across the human and mouse genomes were mapped at a single base-pair resolution and their frequencies were monitored by CAGE (Cap Analysis of Gene Expression) coupled with single-molecule sequencing. Approximately three thousands of samples, consisting of a variety of primary cells, tissues, cell lines, and time series samples during cell activation and development, were subjected to a uniform pipeline of CAGE data production. The analysis pipeline started by measuring RNA extracts to assess their quality, and continued to CAGE library production by using a robotic or a manual workflow, single molecule sequencing, and computational processing to generate frequencies of transcription initiation. Resulting data represents the consequence of transcriptional regulation in each analyzed state of mammalian cells. Non-overlapping peaks over the CAGE profiles, approximately 200,000 and 150,000 peaks for the human and mouse genomes, were identified and annotated to provide precise location of known promoters as well as novel ones, and to quantify their activities. | |
Banos, G.; Bramis, G.; Bush, S. J.; Clark, E. L.; McCulloch, M. E. B.; Smith, J.; Schulze, G.; Arsenos, G.; Hume, D. A.; Psifidi, A. The genomic architecture of mastitis resistance in dairy sheep (Journal Article) In: BMC Genomics, vol. 18, no. 1, 2017, ISSN: 14712164, (Publisher: BioMed Central Ltd.). @article{banos_genomic_2017,Background: Mastitis is the most prevalent disease in dairy sheep with major economic, hygienic and welfare implications. The disease persists in all dairy sheep production systems despite the implementation of improved management practises. Selective breeding for enhanced mastitis resistance may provide the means to further control the disease. In the present study, we investigated the genetic architecture of four mastitis traits in dairy sheep. Individual animal records for clinical mastitis occurrence and three mastitis indicator traits (milk somatic cell count, total viable bacterial count in milk and the California mastitis test) were collected monthly throughout lactation for 609 ewes of the Greek Chios breed. All animals were genotyped with a custom-made 960-single nucleotide polymorphism (SNP) DNA array based on markers located in quantitative trait loci (QTL) regions for mastitis resistance previously detected in three other distinct dairy sheep populations. Results: Heritable variation and strong positive genetic correlations were estimated for clinical mastitis occurrence and the three mastitis indicator traits. SNP markers significantly associated with these mastitis traits were confirmed on chromosomes 2, 3, 5, 16 and 19. We identified pathways, molecular interaction networks and functional gene clusters for mastitis resistance. Candidate genes within the detected regions were identified based upon analysis of an ovine transcriptional atlas and transcriptome data derived from milk somatic cells. Relevant candidate genes implicated in innate immunity included SOCS2, CTLA4, C6, C7, C9, PTGER4, DAB2, CARD6, OSMR, PLXNC1, IDH1, ICOS, FYB, and LYFR. Conclusions: The results confirmed the presence of animal genetic variability in mastitis resistance and identified genomic regions associated with specific mastitis traits in the Chios sheep. The conserved genetic architecture of mastitis resistance between distinct dairy sheep breeds suggests that across-breed selection programmes would be feasible. © 2017 The Author(s). | |
Bush, S. J.; McCulloch, M. E. B.; Summers, K. M.; Hume, D. A.; Clark, E. L. Integration of quantitated expression estimates from polyA-selected and rRNA-depleted RNA-seq libraries (Journal Article) In: BMC Bioinformatics, vol. 18, no. 1, 2017, ISSN: 14712105, (Publisher: BioMed Central Ltd.). @article{bush_integration_2017,Background: The availability of fast alignment-free algorithms has greatly reduced the computational burden of RNA-seq processing, especially for relatively poorly assembled genomes. Using these approaches, previous RNA-seq datasets could potentially be processed and integrated with newly sequenced libraries. Confounding factors in such integration include sequencing depth and methods of RNA extraction and selection. Different selection methods (typically, either polyA-selection or rRNA-depletion) omit different RNAs, resulting in different fractions of the transcriptome being sequenced. In particular, rRNA-depleted libraries sample a broader fraction of the transcriptome than polyA-selected libraries. This study aimed to develop a systematic means of accounting for library type that allows data from these two methods to be compared. Results: The method was developed by comparing two RNA-seq datasets from ovine macrophages, identical except for RNA selection method. Gene-level expression estimates were obtained using a two-part process centred on the high-speed transcript quantification tool Kallisto. Firstly, a set of reference transcripts was defined that constitute a standardised RNA space, with expression from both datasets quantified against it. Secondly, a simple ratio-based correction was applied to the rRNA-depleted estimates. The outcome is an almost perfect correlation between gene expression estimates, independent of library type and across the full range of levels of expression. Conclusion: A combination of reference transcriptome filtering and a ratio-based correction can create equivalent expression profiles from both polyA-selected and rRNA-depleted libraries. This approach will allow meta-analysis and integration of existing RNA-seq data into transcriptional atlas projects. © 2017 The Author(s). | |
Karagianni, A. E.; Kapetanovic, R.; Summers, K. M.; McGorum, B. C.; Hume, D. A.; Pirie, R. S. Comparative transcriptome analysis of equine alveolar macrophages (Journal Article) In: Equine Veterinary Journal, vol. 49, no. 3, pp. 375–382, 2017, ISSN: 04251644, (Publisher: Equine Veterinary Journal Ltd). @article{karagianni_comparative_2017,Reasons for performing study: Alveolar macrophages (AMs) are the first line of defence against pathogens in the lungs of all mammalian species and thus may constitute appropriate therapeutic target cells in the treatment and prevention of opportunistic airway infections. Therefore, acquiring a better understanding of equine macrophage biology is of paramount importance in addressing this issue in relation to the horse. Objectives: To compare the transcriptome of equine AMs with that of equine peritoneal macrophages (PMs) and to investigate the effect of lipopolysaccharide (LPS) on equine AM. Study design: Gene expression study of equine AMs. Methods: Cells from both bronchoalveolar and peritoneal lavage fluid were isolated from systemically healthy horses that had been submitted to euthanasia. Cells were cryopreserved. RNA was extracted and comparative microarray analyses were performed in AMs and PMs, and in AMs treated and untreated with LPS. Comparisons with published data derived from human AM studies were made, with particular focus on LPS-induced inflammatory status. Results: The comparison between AMs and PMs revealed the differential basal expression of 451 genes. Gene expression analysis revealed an alternative (M2) macrophage polarisation profile in AMs and a hybrid macrophage activation profile in PMs, a phenomenon potentially attributable to a degree of induced endotoxin tolerance. The gene expression profile of equine AMs following LPS stimulation revealed significant changes in the expression of 240 genes, including well-known upregulated inflammatory genes. This LPS-induced gene expression profile of equine AMs more closely resembles that of human rather than murine macrophages. Conclusions: This study improves current understanding of equine macrophage biology. These data suggest that the horse may represent a suitable animal model for the study of human macrophage-associated lung inflammation and data derived from human macrophage studies may have significant relevance to the horse. © 2016 The Authors Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd. | |
Kwok, J.; O'Shea, M.; Hume, D. A.; Lengeling, A. Jmjd6, a JmjC dioxygenase with many interaction partners and pleiotropic functions (Journal Article) In: Frontiers in Genetics, vol. 8, no. MAR, 2017, ISSN: 16648021, (Publisher: Frontiers Media S.A.). @article{kwok_jmjd6_2017,Lysyl hydroxylation and arginyl demethylation are post-translational events that are important for many cellular processes. The jumonji domain containing protein 6 (JMJD6) has been reported to catalyze both lysyl hydroxylation and arginyl demethylation on diverse protein substrates. It also interacts directly with RNA. This review summarizes knowledge of JMJD6 functions that have emerged in the last 15 years and considers how a single Jumonji C (JmjC) domain-containing enzyme can target so many different substrates. New links and synergies between the three main proposed functions of Jmjd6 in histone demethylation, promoter proximal pause release of polymerase II and RNA splicing are discussed. The physiological context of the described molecular functions is considered and recently described novel roles for JMJD6 in cancer and immune biology are reviewed. The increased knowledge of JMJD6 functions has wider implications for our general understanding of the JmjC protein family of which JMJD6 is a member. © 2017 Kwok, O'Shea, Hume and Lengeling. | |
Baillie, J. K.; Arner, E.; Daub, C.; Hoon, M. De; Itoh, M.; Kawaji, H.; Lassmann, T.; Carninci, P.; Forrest, A. R. R.; Hayashizaki, Y.; Consortium, FANTOM; Faulkner, G. J.; Wells, C. A.; Rehli, M.; Pavli, P.; Summers, K. M.; Hume, D. A. In: PLoS Genetics, vol. 13, no. 3, 2017, ISSN: 15537390, (Publisher: Public Library of Science). @article{baillie_analysis_2017,The FANTOM5 consortium utilised cap analysis of gene expression (CAGE) to provide an unprecedented insight into transcriptional regulation in human cells and tissues. In the current study, we have used CAGE-based transcriptional profiling on an extended dense time course of the response of human monocyte-derived macrophages grown in macrophage colony-stimulating factor (CSF1) to bacterial lipopolysaccharide (LPS). We propose that this system provides a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. The response to LPS is shown to be a cascade of successive waves of transient gene expression extending over at least 48 hours, with hundreds of positive and negative regulatory loops. Promoter analysis using motif activity response analysis (MARA) identified some of the transcription factors likely to be responsible for the temporal profile of transcriptional activation. Each LPS-inducible locus was associated with multiple inducible enhancers, and in each case, transient eRNA transcription at multiple sites detected by CAGE preceded the appearance of promoter-associated transcripts. LPS-inducible long non-coding RNAs were commonly associated with clusters of inducible enhancers. We used these data to re-examine the hundreds of loci associated with susceptibility to inflammatory bowel disease (IBD) in genome-wide association studies. Loci associated with IBD were strongly and specifically (relative to rheumatoid arthritis and unrelated traits) enriched for promoters that were regulated in monocyte differentiation or activation. Amongst previously-identified IBD susceptibility loci, the vast majority contained at least one promoter that was regulated in CSF1-dependent monocyte-macrophage transitions and/or in response to LPS. On this basis, we concluded that IBD loci are strongly-enriched for monocyte-specific genes, and identified at least 134 additional candidate genes associated with IBD susceptibility from reanalysis of published GWA studies. We propose that dysregulation of monocyte adaptation to the environment of the gastrointestinal mucosa is the key process leading to inflammatory bowel disease. © 2017 Baillie et al. | |
Hume, D. A.; Summers, K. M.; Rehli, M. Transcriptional regulation and macrophage differentiation (Book) wiley, 2017, ISBN: 978-1-68367-066-7 978-1-55581-918-7, (Publication Title: Myeloid Cells in Health and Disease: A Synthesis). @book{hume_transcriptional_2017,The mononuclear phagocyte system (MPS) was originally defined by van Furth and Cohn (1) as a family of cells of the innate immune system derived from hematopoietic progenitor cells under the influence of specific growth factors (2, 3). Differentiated cells of the MPS, monocytes and macrophages, are effectors of innate immunity, engulfing and killing pathogens. They are also needed for tissue repair and resolution of inflammation and for the generation of an appropriate acquired immune response. Their biology and differentiation have been reviewed by a number of authors (2, 4 - 8). The original definition of the MPS considered an essentially linear sequence from pluripotent progenitors, through committed myeloid progenitors shared with granulocytes, to promonocytes and blood monocytes, and thence to tissue macrophages (2, 4 - 8). Resident macrophages differ in function between tissues, and within tissues they occupy a specific niche (9). In some locations, for example, associated with epithelia, they clearly have individual identifiable territories that form a regular pattern (2, 3). © 2017 American Society for Microbiology, Washington, DC. | |
Cordes, M.; Hume, D. Stability and the Morse boundary: (Journal Article) In: Journal of the London Mathematical Society, vol. 95, no. 3, pp. 963–988, 2017, ISSN: 00246107, (Publisher: John Wiley and Sons Ltd.). @article{cordes_stability_2017,Stable subgroups and the Morse boundary are two systematic approaches to collect and study the hyperbolic aspects of finitely generated groups. In this paper we unify and generalise these strategies by viewing any geodesic metric space as a countable union of stable subspaces: we show that every stable subgroup is a quasi-convex subset of a set in this collection and that the Morse boundary is recovered as the direct limit of the usual Gromov boundaries of these hyperbolic subspaces. We use this approach, together with results of Leininger-Schleimer, to deduce that there is no purely geometric obstruction to the existence of a non-virtually-free convex cocompact subgroup of a mapping class group. In addition, we define two new quasi-isometry invariant notions of dimension: the stable dimension, which measures the maximal asymptotic dimension of a stable subset; and the Morse capacity dimension, which naturally generalises Buyalo's capacity dimension for boundaries of hyperbolic spaces. We prove that every stable subset of a right-angled Artin group is quasi-isometric to a tree; and that the stable dimension of a mapping class group is bounded from above by a multiple of the complexity of the surface. In the case of relatively hyperbolic groups we show that finite stable dimension is inherited from peripheral subgroups. Finally, we show that all classical small cancellation groups and certain graphical small cancellation groups - including some Gromov monster groups - have stable dimension at most 2. © 2017 London Mathematical Society. | |
Arzhantseva, G. N.; Cashen, C. H.; Gruber, D.; Hume, D. Characterizations of Morse quasi-geodesics via superlinear divergence and sublinear contraction (Journal Article) In: Documenta Mathematica, vol. 22, no. 2017, pp. 1193–1224, 2017, ISSN: 14310635, (Publisher: Deutsche Mathematiker Vereinigung). @article{arzhantseva_characterizations_2017,We introduce and begin a systematic study of sublinearly contracting projections. We give two characterizations of Morse quasi-geodesics in an arbitrary geodesic metric space. One is that they are sublinearly contracting; the other is that they have completely superlinear divergence. We give a further characterization of sublinearly contracting projections in terms of projections of geodesic segments. | |
Rojo, R.; Pridans, C.; Langlais, D.; Hume, D. A. Transcriptional mechanisms that control expression of the macrophage colony-stimulating factor receptor locus (Journal Article) In: Clinical Science, vol. 131, no. 16, pp. 2161–2182, 2017, ISSN: 01435221, (Publisher: Portland Press Ltd). @article{rojo_transcriptional_2017,The proliferation, differentiation, and survival of cells of the macrophage lineage depends upon signals from the macrophage colony-stimulating factor (CSF) receptor (CSF1R). CSF1R is expressed by embryonic macrophages and induced early in adult hematopoiesis, upon commitment of multipotent progenitors to the myeloid lineage. Transcriptional activation of CSF1R requires interaction between members of the E26 transformation-specific family of transcription factors (Ets) (notably PU.1), C/EBP, RUNX, AP-1/ATF, interferon regulatory factor (IRF), STAT, KLF, REL, FUS/TLS (fused in sarcoma/ranslocated in liposarcoma) families, and conserved regulatory elements within the mouse and human CSF1R locus. One element, the Fms-intronic regulatory element (FIRE), within intron 2, is conserved functionally across all the amniotes. Lineage commitment in multipotent progenitors also requires down-regulation of specific transcription factors such as MYB, FLI1, basic leucine zipper transcriptional factor ATF-like (BATF3), GATA-1, and PAX5 that contribute to differentiation of alternative lineages and repress CSF1R transcription. Many of these transcription factors regulate each other, interact at the protein level, and are themselves downstream targets of CSF1R signaling. Control of CSF1R transcription involves feed-forward and feedback signaling in which CSF1R is both a target and a participant; and dysregulation of CSF1R expression and/or function is associated with numerous pathological conditions. In this review, we describe the regulatory network behind CSF1R expression during differentiation and development of cells of the mononuclear phagocyte system. © 2017 The Author(s). | |
Hume, D. Embedding mapping class groups into a finite product of trees (Journal Article) In: Groups, Geometry, and Dynamics, vol. 11, no. 2, pp. 613–647, 2017, ISSN: 16617207, (Publisher: European Mathematical Society Publishing House). @article{hume_embedding_2017,We prove the equivalence between a relative bottleneck property and being quasi-isometric to a tree-graded space. As a consequence, we deduce that the quasi-trees of spaces defined axiomatically by Bestvina-Bromberg-Fujiwara are quasi-isometric to tree-graded spaces. Using this we prove that mapping class groups quasi-isometrically embed into a finite product of simplicial trees. In particular, these groups have finite Assouad-Nagata dimension, direct embeddings exhibiting p compression exponent 1 for all p 1 and they quasi-isometrically embed into 1.N/. We deduce similar consequences for relatively hyperbolic groups whose parabolic subgroups satisfy such conditions. In obtaining these resultswe also demonstrate that curve complexes of compact surfaces and coned-o graphs of relatively hyperbolic groups admit quasi-isometric embeddings into finite products of trees. © European Mathematical Society. | |
Hume, D. A continuum of expanders (Journal Article) In: Fundamenta Mathematicae, vol. 238, no. 2, pp. 143–152, 2017, ISSN: 00162736, (Publisher: Instytut Matematyczny). @article{hume_continuum_2017,A regular equivalence between two graphs is a pair of uniformly proper Lipschitz maps VV and VV. Using separation profiles we prove that there are 2N0 regular equivalence classes of expander graphs, and of finitely generated groups with a representative which isometrically contains expanders. © Instytut Matematyczny PAN, 2017. | |
Kaur, S.; Raggatt, L. J.; Batoon, L.; Hume, D. A.; Levesque, J. -P.; Pettit, A. R. Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches (Journal Article) In: Seminars in Cell and Developmental Biology, vol. 61, pp. 12–21, 2017, ISSN: 10849521, (Publisher: Academic Press). @article{kaur_role_2017,Macrophages, named for their phagocytic ability, participate in homeostasis, tissue regeneration and inflammatory responses. Bone and adjacent marrow contain multiple functionally unique resident tissue macrophage subsets which maintain and regulate anatomically distinct niche environments within these interconnected tissues. Three subsets of bone–bone marrow resident tissue macrophages have been characterised; erythroblastic island macrophages, haematopoietic stem cell niche macrophages and osteal macrophages. The role of these macrophages in controlling homeostasis and repair in bone and bone marrow niches is reviewed in detail. © 2016 Elsevier Ltd | |
Alexander, K. A.; Raggatt, L. -J.; Millard, S.; Batoon, L.; Wu, A. Chiu-Ku; Chang, M. -K.; Hume, D. A.; Pettit, A. R. Resting and injury-induced inflamed periosteum contain multiple macrophage subsets that are located at sites of bone growth and regeneration (Journal Article) In: Immunology and Cell Biology, vol. 95, no. 1, pp. 7–16, 2017, ISSN: 08189641, (Publisher: Nature Publishing Group). @article{alexander_resting_2017,Better understanding of bone growth and regeneration mechanisms within periosteal tissues will improve understanding of bone physiology and pathology. Macrophage contributions to bone biology and repair have been established but specific investigation of periosteal macrophages has not been undertaken. We used an immunohistochemistry approach to characterize macrophages in growing murine bone and within activated periosteum induced in a mouse model of bone injury. Osteal tissue macrophages (osteomacs) and resident macrophages were distributed throughout resting periosteum. In tissues collected from 4-week-old mice, osteomacs were observed intimately associated with sites of periosteal diaphyseal and metaphyseal bone dynamics associated with normal growth. This included F4/80 + Mac-2 -/low osteomac association with extended tracks of bone formation (modeling) on diphyseal periosteal surfaces. Although this recapitulated endosteal osteomac characteristics, there was subtle variance in the morphology and spatial organization of periosteal modeling-associated osteomacs, which likely reflects the greater structural complexity of periosteum. Osteomacs, resident macrophages and inflammatory macrophages (F4/80 + Mac-2 hi) were associated with the complex bone dynamics occurring within the periosteum at the metaphyseal corticalization zone. These three macrophage subsets were also present within activated native periosteum after bone injury across a 9-day time course that spanned the inflammatory through remodeling bone healing phases. This included osteomac association with foci of endochondral ossification within the activated native periosteum. These observations confirm that osteomacs are key components of both osteal tissues, in spite of salient differences between endosteal and periosteal structure and that multiple macrophage subsets are involved in periosteal bone dynamics. © 2017 Australasian Society for Immunology Inc. All rights reserved. | |
2016 |
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Donaldson, David S.; Sehgal, Anuj; Rios, Daniel; Williams, Ifor R.; Mabbott, Neil A. Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility (Journal Article) In: PLOS Pathogens, vol. 12, no. 12, pp. e1006075, 2016, ISSN: 1553-7374. @article{donaldson_increased_2016, | |
Stevens, M.; Vervelde, L.; Hume, D. Professor Pete Kaiser 1964-2016 (Journal Article) In: Avian pathology : journal of the W.V.P.A, vol. 45, no. 6, pp. 683–684, 2016, ISSN: 14653338. @article{stevens_professor_2016, | |
Wu, Z.; Hu, T.; Rothwell, L.; Vervelde, L.; Kaiser, P.; Boulton, K.; Nolan, M. J.; Tomley, F. M.; Blake, D. P.; Hume, D. A. Analysis of the function of IL-10 in chickens using specific neutralising antibodies and a sensitive capture ELISA (Journal Article) In: Developmental and Comparative Immunology, vol. 63, pp. 206–212, 2016, ISSN: 0145305X, (Publisher: Elsevier Ltd). @article{wu_analysis_2016,In mammals, the inducible cytokine interleukin 10 is a feedback negative regulator of inflammation. To determine the extent to which this function is conserved in birds, recombinant chicken IL-10 was expressed as a secreted human Ig Fc fusion protein (chIL-10-Fc) and used to immunise mice. Five monoclonal antibodies (mAb) which specifically recognise chicken IL-10 were generated and characterised. Two capture ELISA assays were developed which detected native chIL-10 secreted from chicken bone marrow-derived macrophages (chBMMs) stimulated with lipopolysaccharide (LPS). Three of the mAbs detected intracellular IL-10. This was detected in only a subset of the same LPS-stimulated chBMMs. The ELISA assay also detected massive increases in circulating IL-10 in chickens challenged with the coccidial parasite, Eimeria tenella. The same mAbs neutralised the bioactivity of recombinant chIL-10. The role of IL-10 in feedback control was tested in vitro. The neutralising antibodies prevented IL-10-induced inhibition of IFN-γ synthesis by mitogen-activated lymphocytes and increased nitric oxide production in LPS-stimulated chBMMs. The results confirm that IL-10 is an inducible feedback regulator of immune response in chickens, and could be the target for improved vaccine efficacy or breeding strategies. © 2016 The Authors | |
Psifidi, A.; Banos, G.; Matika, O.; Desta, T. T.; Bettridge, J.; Hume, D. A.; Dessie, T.; Christley, R.; Wigley, P.; Hanotte, O.; Kaiser, P. Genome-wide association studies of immune, disease and production traits in indigenous chicken ecotypes (Journal Article) In: Genetics Selection Evolution, vol. 48, no. 1, 2016, ISSN: 0999193X, (Publisher: BioMed Central Ltd.). @article{psifidi_genome-wide_2016,Background: The majority of chickens in sub-Saharan Africa are indigenous ecotypes, well adapted to the local environment and raised in scavenging production systems. Although they are generally resilient to disease challenge, routine vaccination and biosecurity measures are rarely applied and infectious diseases remain a major cause of mortality and reduced productivity. Management and genetic improvement programmes are hampered by lack of routine data recording. Selective breeding based on genomic technologies may provide the means to enhance sustainability. In this study, we investigated the genetic architecture of antibody response to four major infectious diseases [infectious bursal disease (IBDV), Marek’s disease (MDV), fowl typhoid (SG), fowl cholera (PM)] and resistance to Eimeria and cestode parasitism, along with two production traits [body weight and body condition score (BCS)] in two distinct indigenous Ethiopian chicken ecotypes. We conducted variance component analyses, genome-wide association studies, and pathway and selective sweep analyses. Results: The large majority of birds was found to have antibody titres for all pathogens and were infected with both parasites, suggesting almost universal exposure. We derived significant moderate to high heritabilities for IBDV, MDV and PM antibody titres, cestodes infestation, body weight and BCS. We identified single nucleotide polymorphisms (SNPs) with genome-wide significance for each trait. Based on these associations, we identified for each trait, pathways, networks and functional gene clusters that include plausible candidate genes. Selective sweep analyses revealed a locus on chromosome 18 associated with viral antibody titres and resistance to Eimeria parasitism that is within a positive selection signal. We found no significant genetic correlations between production, immune and disease traits, implying that selection for altered antibody response and/or disease resistance will not affect production. Conclusions: We confirmed the presence of genetic variability and identified SNPs significantly associated with immune, disease and production traits in indigenous village chickens. Results underpin the feasibility of concomitant genetic improvement for enhanced antibody response, resistance to parasitism and productivity within and across indigenous chicken ecotypes. © 2016 The Author(s). | |
Pridans, C.; Davis, G. M.; Sauter, K. A.; Lisowski, Z. M.; Corripio-Miyar, Y.; Raper, A.; Lefevre, L.; Young, R.; McCulloch, M. E.; Lillico, S.; Milne, E.; Whitelaw, B.; Hume, D. A. A Csf1r-EGFP transgene provides a novel marker for monocyte subsets in sheep (Journal Article) In: Journal of Immunology, vol. 197, no. 6, pp. 2297–2305, 2016, ISSN: 00221767, (Publisher: American Association of Immunologists). @article{pridans_csf1r-egfp_2016,Expression of Csf1r in adults is restricted to cells of the macrophage lineage. Transgenic reporters based upon the Csf1r locus require inclusion of the highly conserved Fms-intronic regulatory element for expression.We have created Csf1r-EGFP transgenic sheep via lentiviral transgenesis of a construct containing elements of the mouse Fms-intronic regulatory element and Csf1r promoter. Committed bone marrow macrophage precursors and blood monocytes express EGFP in these animals. Sheep monocytes were divided into three populations, similar to classical, intermediate, and nonclassical monocytes in humans, based upon CD14 and CD16 expression. All expressed EGFP, with increased levels in the nonclassical subset. Because Csf1r expression coincides with the earliest commitment to the macrophage lineage, Csf1r-EGFP bone marrow provides a tool for studying the earliest events in myelopoiesis using the sheep as a model. Copyright © 2016 by The American Association of Immunologists, Inc. | |
Hu, T.; Wu, Z.; Vervelde, L.; Rothwell, L.; Hume, D. A.; Kaiser, P. Functional annotation of the Ŧ-cell immunoglobulin mucin family in birds (Journal Article) In: Immunology, vol. 148, no. 3, pp. 287–303, 2016, ISSN: 00192805, (Publisher: Blackwell Publishing Ltd). @article{hu_functional_2016,T-cell immunoglobulin and mucin (TIM) family molecules are cell membrane proteins, preferentially expressed on various immune cells and implicated in recognition and clearance of apoptotic cells. Little is known of their function outside human and mouse, and nothing outside mammals. We identified only two TIM genes (chTIM) in the chicken genome, putative orthologues of mammalian TIM1 and TIM4, and cloned the respective cDNAs. Like mammalian TIM1, chTIM1 expression was restricted to lymphoid tissues and immune cells. The gene chTIM4 encodes at least five splice variants with distinct expression profiles that also varied between strains of chicken. Expression of chTIM4 was detected in myeloid antigen-presenting cells, and in γδ T cells, whereas mammalian TIM4 is not expressed in T cells. Like the mammalian proteins, chTIM1 and chTIM4 fusion proteins bind to phosphatidylserine, and are thereby implicated in recognition of apoptotic cells. The chTIM4–immunoglobulin fusion protein also had co-stimulatory activity on chicken T cells, suggesting a function in antigen presentation. © 2016 The Authors. Immunology published by John Wiley & Sons Ltd. | |
Vitak, N.; Hume, D. A.; Chappell, K. J.; Sester, D. P.; Stacey, K. J. Induction of interferon and cell death in response to cytosolic DNA in chicken macrophages (Journal Article) In: Developmental and Comparative Immunology, vol. 59, pp. 145–152, 2016, ISSN: 0145305X, (Publisher: Elsevier Ltd). @article{vitak_induction_2016,Responses to cytosolic DNA can protect against both infectious organisms and the mutagenic effect of DNA integration. Recognition of invading DNA is likely to be fundamental to eukaryotic cellular life, but has been described only in mammals. Introduction of DNA into chicken macrophages induced type I interferon mRNA via a pathway conserved with mammals, requiring the receptor cGAS and the signalling protein STING. A second pathway of cytosolic DNA recognition in mammalian macrophages, initiated by absent in melanoma 2 (AIM2), results in rapid inflammasome-mediated pyroptotic cell death. AIM2 is restricted to mammals. Nevertheless, chicken macrophages underwent lytic cell death within 15 min of DNA transfection. The mouse AIM2-mediated response requires double stranded DNA, but chicken cell death was maintained with denatured DNA. This appears to be a novel form of rapid necrotic cell death, which we propose is an ancient response rendered redundant in mammalian macrophages by the appearance of the AIM2 inflammasome. The retention of these cytosolic DNA responses through evolution, with both conserved and non-conserved mechanisms, suggests a fundamental importance in cellular defence. © 2016 Elsevier Ltd. | |
Jubb, A. W.; Young, R. S.; Hume, D. A.; Bickmore, W. A. Enhancer turnover is associated with a divergent transcriptional response to glucocorticoid in mouse and human macrophages (Journal Article) In: Journal of Immunology, vol. 196, no. 2, pp. 813–822, 2016, ISSN: 00221767, (Publisher: American Association of Immunologists). @article{jubb_enhancer_2016,Phenotypic differences between individuals and species are controlled in part through differences in expression of a relatively conserved set of genes. Genes expressed in the immune system are subject to especially powerful selection. We have investigated the evolution of both gene expression and candidate enhancers in human and mouse macrophages exposed to glucocorticoid (GC), a regulator of innate immunity and an important therapeutic agent. Our analyses revealed a very limited overlap in the repertoire of genes responsive to GC in human and mouse macrophages. Peaks of inducible binding of the GC receptor (GR) detected by chromatin immunoprecipitation-Seq correlated with induction, but not repression, of target genes in both species, occurred at distal regulatory sites not promoters, and were strongly enriched for the consensus GR-binding motif. Turnover of GR binding between mice and humans was associated with gain and loss of the motif. There was no detectable signal of positive selection at speciesspecific GR binding sites, but clear evidence of purifying selection at the small number of conserved sites.We conclude that enhancer divergence underlies the difference in transcriptional activation after GC treatment between mouse and human macrophages. Only the shared inducible loci show evidence of selection, and therefore these loci may be important for the subset of responses to GC that is shared between species. © 2016 by The American Association of Immunologists, Inc. | |
Psifidi, A.; Fife, M.; Howell, J.; Matika, O.; Diemen, P. M.; Kuo, R.; Smith, J.; Hocking, P. M.; Salmon, N.; Jones, M. A.; Hume, D. A.; Banos, G.; Stevens, M. P.; Kaiser, P. The genomic architecture of resistance to Campylobacter jejuni intestinal colonisation in chickens (Journal Article) In: BMC Genomics, vol. 17, no. 1, 2016, ISSN: 14712164, (Publisher: BioMed Central Ltd.). @article{psifidi_genomic_2016,Background: Campylobacter is the leading cause of foodborne diarrhoeal illness in humans and is mostly acquired from consumption or handling of contaminated poultry meat. In the absence of effective licensed vaccines and inhibitors, selection for chickens with increased resistance to Campylobacter could potentially reduce its subsequent entry into the food chain. Campylobacter intestinal colonisation levels are influenced by the host genetics of the chicken. In the present study, two chicken populations were used to investigate the genetic architecture of avian resistance to colonisation: (i) a back-cross of two White Leghorn derived inbred lines [(61 x N) x N] known to differ in resistance to Campylobacter colonisation and (ii) a 9th generation advanced intercross (61 x N) line. Results: The level of colonisation with Campylobacter jejuni following experimental infection was found to be a quantitative trait. A back-cross experiment using 1,243 fully informative single nucleotide polymorphism (SNP) markers revealed quantitative trait loci (QTL) on chromosomes 7, 11 and 14. In the advanced intercross line study, the location of the QTL on chromosome 14 was confirmed and refined and two new QTLs were identified located on chromosomes 4 and 16. Pathway and re-sequencing data analysis of the genes located in the QTL candidate regions identified potential pathways, networks and candidate resistance genes. Finally, gene expression analyses were performed for some of the candidate resistance genes to support the results. Conclusion: Campylobacter resistance in chickens is a complex trait, possibly involving the Major Histocompatibility Complex, innate and adaptive immune responses, cadherins and other factors. Two of the QTLs for Campylobacter resistance are co-located with Salmonella resistance loci, indicating that it may be possible to breed simultaneously for enhanced resistance to both zoonoses. © 2016 Psifidi et al. | |
Sauter, K. A.; Waddell, L. A.; Lisowski, Z. M.; Young, R.; Lefevre, L.; Davis, G. M.; Clohisey, S. M.; McCulloch, M.; Magowan, E.; Mabbott, N. A.; Summers, K. M.; Hume, D. A. Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs (Journal Article) In: American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 311, no. 3, pp. G533–G547, 2016, ISSN: 01931857, (Publisher: American Physiological Society). @article{sauter_macrophage_2016,Macrophage colony-stimulating factor (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage. To explore the role of CSF1 in steady-state control of monocyte production and differentiation and tissue repair, we previously developed a bioactive protein with a longer half-life in circulation by fusing pig CSF1 with the Fc region of pig IgG1a. CSF1-Fc administration to pigs expanded progenitor pools in the marrow and selectively increased monocyte numbers and their expression of the maturation marker CD163. There was a rapid increase in the size of the liver, and extensive proliferation of hepatocytes associated with increased macrophage infiltration. Despite the large influx of macrophages, there was no evidence of liver injury and no increase in circulating liver enzymes. Microarray expression profiling of livers identified increased expression of macrophage markers, i.e., cytokines such as TNF, IL1, and IL6 known to influence hepatocyte proliferation, alongside cell cycle genes. The analysis also revealed selective enrichment of genes associated with portal, as opposed to centrilobular regions, as seen in hepatic regeneration. Combined with earlier data from the mouse, this study supports the existence of a CSF1-dependent feedback loop, linking macrophages of the liver with bone marrow and blood monocytes, to mediate homeostatic control of the size of the liver. The results also provide evidence of safety and efficacy for possible clinical applications of CSF1-Fc. © The American Physiological Society. | |
2015 |
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Mabbott, Neil A; Sehgal, Anuj; Donaldson, David S M Cells (Book Section) In: Ltd, John Wiley Sons (Ed.): eLS, pp. 1–9, John Wiley & Sons, Ltd, Chichester, UK, 2015, ISBN: 978-0-470-01590-2 978-0-470-01617-6. @incollection{john_wiley__sons_ltd_m_2015, | |
Mabbott, Neil A.; Kobayashi, Atsushi; Sehgal, Anuj; Bradford, Barry M.; Pattison, Mari; Donaldson, David S. Aging and the mucosal immune system in the intestine (Journal Article) In: Biogerontology, vol. 16, no. 2, pp. 133–145, 2015, ISSN: 1389-5729, 1573-6768. @article{mabbott_aging_2015, | |
Stutchfield, B. M.; Antoine, D. J.; Mackinnon, A. C.; Gow, D. J.; Bain, C. C.; Hawley, C. A.; Hughes, M. J.; Francis, B.; Wojtacha, D.; Man, T. Y.; Dear, J. W.; Devey, L. R.; Mowat, A. M.; Pollard, J. W.; Park, B. K.; Jenkins, S. J.; Simpson, K. J.; Hume, D. A.; Wigmore, S. J.; Forbes, S. J. CSF1 Restores Innate Immunity after Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients with Acute Liver Failure (Journal Article) In: Gastroenterology, vol. 149, no. 7, pp. 1896–1909.e14, 2015, ISSN: 00165085, (Publisher: W.B. Saunders). @article{stutchfield_csf1_2015,Background & Aims Liver regeneration requires functional liver macrophages, which provide an immune barrier that is compromised after liver injury. The numbers of liver macrophages are controlled by macrophage colony-stimulating factor (CSF1). We examined the prognostic significance of the serum level of CSF1 in patients with acute liver injury and studied its effects in mice. Methods We measured levels of CSF1 in serum samples collected from 55 patients who underwent partial hepatectomy at the Royal Infirmary Edinburgh between December 2012 and October 2013, as well as from 78 patients with acetaminophen-induced acute liver failure admitted to the Royal Infirmary Edinburgh or the University of Kansas Medical Centre. We studied the effects of increased levels of CSF1 in uninjured mice that express wild-type CSF1 receptor or a constitutive or inducible CSF1-receptor reporter, as well as in chemokine receptor 2 (Ccr2)-/- mice; we performed fate-tracing experiments using bone marrow chimeras. We administered CSF1-Fc (fragment, crystallizable) to mice after partial hepatectomy and acetaminophen intoxication, and measured regenerative parameters and innate immunity by clearance of fluorescent microbeads and bacterial particles. Results Serum levels of CSF1 increased in patients undergoing liver surgery in proportion to the extent of liver resected. In patients with acetaminophen-induced acute liver failure, a low serum level of CSF1 was associated with increased mortality. In mice, administration of CSF1-Fc promoted hepatic macrophage accumulation via proliferation of resident macrophages and recruitment of monocytes. CSF1-Fc also promoted transdifferentiation of infiltrating monocytes into cells with a hepatic macrophage phenotype. CSF1-Fc increased innate immunity in mice after partial hepatectomy or acetaminophen-induced injury, with resident hepatic macrophage as the main effector cells. Conclusions Serum CSF1 appears to be a prognostic marker for patients with acute liver injury. CSF1 might be developed as a therapeutic agent to restore innate immune function after liver injury. © 2015 AGA Institute. | |
Robert, C.; Kapetanovic, R.; Beraldi, D.; Watson, M.; Archibald, A. L.; Hume, D. A. Identification and annotation of conserved promoters and macrophage-expressed genes in the pig genome (Journal Article) In: BMC Genomics, vol. 16, no. 1, 2015, ISSN: 14712164, (Publisher: BioMed Central Ltd.). @article{robert_identification_2015,Background: The FANTOM5 consortium used Cap Analysis of Gene Expression (CAGE) tag sequencing to produce a comprehensive atlas of promoters and enhancers within the human and mouse genomes. We reasoned that the mapping of these regulatory elements to the pig genome could provide useful annotation and evidence to support assignment of orthology. Results: For human transcription start sites (TSS) associated with annotated human-mouse orthologs, 17% mapped to the pig genome but not to the mouse, 10% mapped only to the mouse, and 55% mapped to both pig and mouse. Around 17% did not map to either species. The mapping percentages were lower where there was not clear orthology relationship, but in every case, mapping to pig was greater than to mouse, and the degree of homology was also greater. Combined mapping of mouse and human CAGE-defined promoters identified at least one putative conserved TSS for textgreater16,000 protein-coding genes. About 54% of the predicted locations of regulatory elements in the pig genome were supported by CAGE and/or RNA-Seq analysis from pig macrophages. Conclusions: Comparative mapping of promoters and enhancers from humans and mice can provide useful preliminary annotation of other animal genomes. The data also confirm extensive gain and loss of regulatory elements between species, and the likelihood that pigs provide a better model than mice for human gene regulation and function. © 2015 Robert et al. | |
Schmid, M.; Smith, J.; Burt, D. W.; Aken, B. L.; Antin, P. B.; Archibald, A. L.; Ashwell, C.; Blackshear, P. J.; Boschiero, C.; Brown, C. T.; Burgess, S. C.; Cheng, H. H.; Chow, W.; Coble, D. J.; Cooksey, A.; Crooijmans, R. P. M. A.; Damas, J.; Davis, R. V. N.; Koning, D. -J. De; Delany, M. E.; Derrien, T.; Desta, T. T.; Dunn, I. C.; Dunn, M.; Ellegren, H.; Eöry, L.; Erb, I.; Farré, M.; Fasold, M.; Fleming, D.; Flicek, P.; Fowler, K. E.; Frésard, L.; Froman, D. P.; Garceau, V.; Gardner, P. P.; Gheyas, A. A.; Griffin, D. K.; Groenen, M. A. M.; Haaf, T.; Hanotte, O.; Hart, A.; Häsler, J.; Hedges, S. B.; Hertel, J.; Howe, K.; Hubbard, A.; Hume, D. A.; Kaiser, P.; Kedra, D.; Kemp, S. J.; Klopp, C.; Kniel, K. E.; Kuo, R.; Lagarrigue, S.; Lamont, S. J.; Larkin, D. M.; Lawal, R. A.; Markland, S. M.; McCarthy, F.; McCormack, H. A.; McPherson, M. C.; Motegi, A.; Muljo, S. A.; Münsterberg, A.; Nag, R.; Nanda, I.; Neuberger, M.; Nitsche, A.; Notredame, C.; Noyes, H.; O'Connor, R.; O'Hare, E. A.; Oler, A. J.; Ommeh, S. C.; Pais, H.; Persia, M.; Pitel, F.; Preeyanon, L.; Barja, P. Prieto; Pritchett, E. M.; Rhoads, D. D.; Robinson, C. M.; Romanov, M. N.; Rothschild, M.; Roux, P. -F.; Schmidt, C. J.; Schneider, A. -S.; Schwartz, M. G.; Searle, S. M.; Skinner, M. A.; Smith, C. A.; Stadler, P. F.; Steeves, T. E.; Steinlein, C.; Sun, L.; Takata, M.; Ulitsky, I.; Wang, Q.; Wang, Y.; Warren, W. C.; Wood, J. M. D.; Wragg, D.; Zhou, H. Third Report on Chicken Genes and Chromosomes 2015: (Journal Article) In: Cytogenetic and Genome Research, vol. 145, no. 2, pp. 78–179, 2015, ISSN: 14248581, (Publisher: S. Karger AG). @article{schmid_third_2015, | |
Rodero, M. P.; Poupel, L.; Loyher, P. -L.; Hamon, P.; Licata, F.; Pessel, C.; Hume, D. A.; Combadière, C.; Boissonnas, A. Immune surveillance of the lung by migrating tissue monocytes (Journal Article) In: eLife, vol. 4, no. JULY 2015, 2015, ISSN: 2050084X, (Publisher: eLife Sciences Publications Ltd). @article{rodero_immune_2015,Monocytes are phagocytic effector cells in the blood and precursors of resident andinflammatory tissue macrophages. The aim of the current study was to analyse and compare their contribution to innate immune surveillance of the lung in the steady state with macrophage anddendritic cells (DC). ECFP and EGFP transgenic reporters based upon Csf1r and Cx3cr1 distinguish monocytes from resident mononuclear phagocytes. We used these transgenes to study the migratory properties of monocytes and macrophages by functional imaging on explanted lungs. Migratory monocytes were found to be either patrolling within large vessels of the lung or locating at the interface between lung capillaries and alveoli. This spatial organisation gives to monocytes the property to capture fluorescent particles derived from both vascular and airway routes. We conclude that monocytes participate in steady-state surveillance of the lung, in a way that is complementary to resident macrophages and DC, without differentiating into macrophages. © Rodero et al. | |
Hume, D. Direct embeddings of relatively hyperbolic groups with optimal ℓp compression exponent (Journal Article) In: Journal fur die Reine und Angewandte Mathematik, vol. 2015, no. 703, pp. 147–172, 2015, ISSN: 00754102, (Publisher: Walter de Gruyter GmbH). @article{hume_direct_2015,We prove that for all p > 1, every relatively hyperbolic group has ℓp compression exponent equal to the minimum of the exponents of its maximal peripheral subgroups. This improves results of Dadarlat-Guentner and Dreesen. As a first step we give a direct geometric proof that hyperbolic groups have ℓp compression exponent 1, independent of those given by Bonk-Schramm, Buyalo-Dranishnikov-Schroeder, Gal and Tessera. © 2015 by De Gruyter. | |
Hume, D. Plant breeding: UK bioscientists push for crop policy (Journal Article) In: Nature, vol. 521, no. 7553, pp. 423, 2015, ISSN: 00280836, (Publisher: Nature Publishing Group). @article{hume_plant_2015, | |
Joshi, A.; Pooley, C.; Freeman, T. C.; Lennartsson, A.; Babina, M.; Schmidl, C.; Geijtenbeek, T.; Michoel, T.; Severin, J.; Itoh, M.; Lassmann, T.; Kawaji, H.; Hayashizaki, Y.; Carninci, P.; Forrest, A. R. R.; Rehli, M.; Hume, D. A.; Consortium, Fantom Technical advance: Transcription factor, promoter, and enhancer utilization in human myeloid cells (Journal Article) In: Journal of Leukocyte Biology, vol. 97, no. 5, pp. 985–995, 2015, ISSN: 07415400, (Publisher: John Wiley and Sons Inc.). @article{joshi_technical_2015,The generation of myeloid cells from their progenitors is regulated at the level of transcription by combinatorial control of key transcription factors influencing cell-fate choice. To unravel the global dynamics of this process at the transcript level, we generated transcription profiles for 91 human cell types of myeloid origin by use of CAGE profiling. The CAGE sequencing of these samples has allowed us to investigate diverse aspects of transcription control during myelopoiesis, such as identification of novel transcription factors, miRNAs, and noncoding RNAs specific to the myeloid lineage. We further reconstructed a transcription regulatory network by clustering coexpressed transcripts and associating them with enriched cis-regulatory motifs. With the use of the bidirectional expression as a proxy for enhancers, we predicted over 2000 novel enhancers, including an enhancer 38 kb downstream of IRF8 and an intronic enhancer in the KIT gene locus. Finally, we highlighted relevance of these data to dissect transcription dynamics during progressive maturation of granulocyte precursors. A multifaceted analysis of the myeloid transcriptome ismade available (www.myeloidome.roslin.ed.ac. uk). This high-quality dataset provides a powerful resource to study transcriptional regulation during myelopoiesis and to infer the likely functions of unannotated genes in human innate immunity. © Society for Leukocyte Biology. | |
Aitken, S.; Magi, S.; Alhendi, A. M. N.; Itoh, M.; Kawaji, H.; Lassmann, T.; Daub, C. O.; Arner, E.; Carninci, P.; Forrest, A. R. R.; Hayashizaki, Y.; the FANTOM Consortium,; Khachigian, L. M.; Okada-Hatakeyama, M.; Semple, C. A.; Sandelin, A.; Wells, C.; Hume, D. A.; Summers, K. M.; Vitting-Seerup, K.; Andersson, R.; Yumoto, M. N. Transcriptional Dynamics Reveal Critical Roles for Non-coding RNAs in the Immediate-Early Response (Journal Article) In: PLoS Computational Biology, vol. 11, no. 4, 2015, ISSN: 1553734X, (Publisher: Public Library of Science). @article{aitken_transcriptional_2015,The immediate-early response mediates cell fate in response to a variety of extracellular stimuli and is dysregulated in many cancers. However, the specificity of the response across stimuli and cell types, and the roles of non-coding RNAs are not well understood. Using a large collection of densely-sampled time series expression data we have examined the induction of the immediate-early response in unparalleled detail, across cell types and stimuli. We exploit cap analysis of gene expression (CAGE) time series datasets to directly measure promoter activities over time. Using a novel analysis method for time series data we identify transcripts with expression patterns that closely resemble the dynamics of known immediate-early genes (IEGs) and this enables a comprehensive comparative study of these genes and their chromatin state. Surprisingly, these data suggest that the earliest transcriptional responses often involve promoters generating non-coding RNAs, many of which are produced in advance of canonical protein-coding IEGs. IEGs are known to be capable of induction without de novo protein synthesis. Consistent with this, we find that the response of both protein-coding and non-coding RNA IEGs can be explained by their transcriptionally poised, permissive chromatin state prior to stimulation. We also explore the function of non-coding RNAs in the attenuation of the immediate early response in a small RNA sequencing dataset matched to the CAGE data: We identify a novel set of microRNAs responsible for the attenuation of the IEG response in an estrogen receptor positive cancer cell line. Our computational statistical method is well suited to meta-analyses as there is no requirement for transcripts to pass thresholds for significant differential expression between time points, and it is agnostic to the number of time points per dataset. © 2015 Aitken et al. | |
Ford, C. A.; Petrova, S.; Pound, J. D.; Voss, J. J. L. P.; Melville, L.; Paterson, M.; Farnworth, S. L.; Gallimore, A. M.; Cuff, S.; Wheadon, H.; Dobbin, E.; Ogden, C. A.; Dumitriu, I. E.; Dunbar, D. R.; Murray, P. G.; Ruckerl, D.; Allen, J. E.; Hume, D. A.; Rooijen, N. Van; Goodlad, J. R.; Freeman, T. C.; Gregory, C. D. Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma (Journal Article) In: Current Biology, vol. 25, no. 5, pp. 577–588, 2015, ISSN: 09609822, (Publisher: Cell Press). @article{ford_oncogenic_2015,Background Cells undergoing apoptosis are known to modulate their tissue microenvironments. By acting on phagocytes, notably macrophages, apoptotic cells inhibit immunological and inflammatory responses and promote trophic signaling pathways. Paradoxically, because of their potential to cause death of tumor cells and thereby militate against malignant disease progression, both apoptosis and tumor-associated macrophages (TAMs) are often associated with poor prognosis in cancer. We hypothesized that, in progression of malignant disease, constitutive loss of a fraction of the tumor cell population through apoptosis could yield tumor-promoting effects. Results Here, we demonstrate that apoptotic tumor cells promote coordinated tumor growth, angiogenesis, and accumulation of TAMs in aggressive B cell lymphomas. Through unbiased "in situ transcriptomics" analysis - gene expression profiling of laser-captured TAMs to establish their activation signature in situ - we show that these cells are activated to signal via multiple tumor-promoting reparatory, trophic, angiogenic, tissue remodeling, and anti-inflammatory pathways. Our results also suggest that apoptotic lymphoma cells help drive this signature. Furthermore, we demonstrate that, upon induction of apoptosis, lymphoma cells not only activate expression of the tumor-promoting matrix metalloproteinases MMP2 and MMP12 in macrophages but also express and process these MMPs directly. Finally, using a model of malignant melanoma, we show that the oncogenic potential of apoptotic tumor cells extends beyond lymphoma. Conclusions In addition to its profound tumor-suppressive role, apoptosis can potentiate cancer progression. These results have important implications for understanding the fundamental biology of cell death, its roles in malignant disease, and the broader consequences of apoptosis-inducing anti-cancer therapy. © 2015 Elsevier Ltd All rights reserved. | |
Garcia-Morales, C.; Nandi, S.; Zhao, D.; Sauter, K. A.; Vervelde, L.; McBride, D.; Sang, H. M.; Clinton, M.; Hume, D. A. Cell-autonomous sex differences in gene expression in chicken bone marrow-derived macrophages (Journal Article) In: Journal of Immunology, vol. 194, no. 5, pp. 2338–2344, 2015, ISSN: 00221767, (Publisher: American Association of Immunologists). @article{garcia-morales_cell-autonomous_2015,We have identified differences in gene expression in macrophages grown from the bone marrow of male and female chickens in recombinant chicken M-CSF (CSF1). Cells were profiled with or without treatment with bacterial LPS for 24 h. Approximately 600 transcripts were induced by prolonged LPS stimulation to an equal extent in the male and female macrophages. Many transcripts encoded on the Z chromosome were expressed ∼1.6-fold higher in males, reflecting a lack of dosage compensation in the homogametic sex. A smaller set of W chromosome-specific genes was expressed only in females. LPS signaling in mammals is associated with induction of type 1 IFN-responsive genes. Unexpectedly, because IFNs are encoded on the Z chromosome of chickens, unstimulated macrophages from the female birds expressed a set of known IFN-inducible genes at much higher levels than male cells under the same conditions. To confirm that these differences were not the consequence of the actions of gonadal hormones, we induced gonadal sex reversal to alter the hormonal environment of the developing chick and analyzed macrophages cultured from male, female, and female sex-reversed embryos. Gonadal sex reversal did not alter the sexually dimorphic expression of either sex-linked or IFN-responsive genes. We suggest that female birds compensate for the reduced dose of inducible IFN with a higher basal set point of IFN-responsive genes. Copyright © 2015 The Authors | |
Arner, E.; Daub, C. O.; Vitting-Seerup, K.; Andersson, R.; Lilje, B.; Drabløs, F.; Lennartsson, A.; Rönnerblad, M.; Hrydziuszko, O.; Vitezic, M.; Freeman, T. C.; Alhendi, A. M. N.; Arner, P.; Axton, R.; Baillie, J. K.; Beckhouse, A.; Bodega, B.; Briggs, J.; Brombacher, F.; Davis, M.; Detmar, M.; Ehrlund, A.; Endoh, M.; Eslami, A.; Fagiolini, M.; Fairbairn, L.; Faulkner, G. J.; Ferrai, C.; Fisher, M. E.; Forrester, L.; Goldowitz, D.; Guler, R.; Ha, T.; Hara, M.; Herlyn, M.; Ikawa, T.; Kai, C.; Kawamoto, H.; Khachigian, L. M.; Klinken, S. P.; Kojima, S.; Koseki, H.; Klein, S.; Mejhert, N.; Miyaguchi, K.; Mizuno, Y.; Morimoto, M.; Morris, K. J.; Mummery, C.; Nakachi, Y.; Ogishima, S.; Okada-Hatakeyama, M.; Okazaki, Y.; Orlando, V.; Ovchinnikov, D.; Passier, R.; Patrikakis, M.; Pombo, A.; Qin, X. -Y.; Roy, S.; Sato, H.; Savvi, S.; Saxena, A.; Schwegmann, A.; Sugiyama, D.; Swoboda, R.; Tanaka, H.; Tomoiu, A.; Winteringham, L. N.; Wolvetang, E.; Yanagi-Mizuochi, C.; Yoneda, M.; Zabierowski, S.; Zhang, P.; Abugessaisa, I.; Bertin, N.; Diehl, A. D.; Fukuda, S.; Furuno, M.; Harshbarger, J.; Hasegawa, A.; Hori, F.; Ishikawa-Kato, S.; Ishizu, Y.; Itoh, M.; Kawashima, T.; Kojima, M.; Kondo, N.; Lizio, M.; Meehan, T. F.; Mungall, C. J.; Murata, M.; Nishiyori-Sueki, H.; Sahin, S.; Nagao-Sato, S.; Severin, J.; Hoon, M. J. L. De; Kawai, J.; Kasukawa, T.; Lassmann, T.; Suzuki, H.; Kawaji, H.; Summers, K. M.; Wells, C.; Hume, D. A.; Forrest, A. R. R.; Sandelin, A.; Carninci, P.; Hayashizaki, Y.; Consortium, FANTOM Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells (Journal Article) In: Science, vol. 347, no. 6225, pp. 1010–1014, 2015, ISSN: 00368075, (Publisher: American Association for the Advancement of Science). @article{arner_transcribed_2015,Although it is generally accepted that cellular differentiation requires changes to transcriptional networks, dynamic regulation of promoters and enhancers at specific sets of genes has not been previously studied en masse. Exploiting the fact that active promoters and enhancers are transcribed, we simultaneously measured their activity in 19 human and 14 mouse time courses covering a wide range of cell types and biological stimuli. Enhancer RNAs, then messenger RNAs encoding transcription factors, dominated the earliest responses. Binding sites for key lineage transcription factors were simultaneously overrepresented in enhancers and promoters active in each cellular system. Our data support a highly generalizable model in which enhancer transcription is the earliest event in successive waves of transcriptional change during cellular differentiation or activation. © 2015, American Association for the Advancement of Science. All rights reserved. | |
Garceau, V.; Balic, A.; Garcia-Morales, C.; Sauter, K. A.; McGrew, M. J.; Smith, J.; Vervelde, L.; Sherman, A.; Fuller, T. E.; Oliphant, T.; Shelley, J. A.; Tiwari, R.; Wilson, T. L.; Chintoan-Uta, C.; Burt, D. W.; Stevens, M. P.; Sang, H. M.; Hume, D. A. The development and maintenance of the mononuclear phagocyte system of the chick is controlled by signals from the macrophage colony-stimulating factor receptor (Journal Article) In: BMC Biology, vol. 13, no. 1, 2015, ISSN: 17417007, (Publisher: BioMed Central Ltd.). @article{garceau_development_2015,Macrophages have many functions in development and homeostasis as well as innate immunity. Recent studies in mammals suggest that cells arising in the yolk sac give rise to self-renewing macrophage populations that persist in adult tissues. Macrophage proliferation and differentiation is controlled by macrophage colony-stimulating factor (CSF1) and interleukin 34 (IL34), both agonists of the CSF1 receptor (CSF1R). In the current manuscript we describe the origin, function and regulation of macrophages, and the role of CSF1R signaling during embryonic development, using the chick as a model. Results: Based upon RNA-sequencing comparison to bone marrow-derived macrophages grown in CSF1, we show that embryonic macrophages contribute around 2% of the total embryo RNA in day 7 chick embryos, and have similar gene expression profiles to bone marrow-derived macrophages. To explore the origins of embryonic and adult macrophages, we injected Hamburger-Hamilton stage 16 to 17 chick embryos with either yolk sac-derived blood cells, or bone marrow cells from EGFP+ donors. In both cases, the transferred cells gave rise to large numbers of EGFP+ tissue macrophages in the embryo. In the case of the yolk sac, these cells were not retained in hatched birds. Conversely, bone marrow EGFP+ cells gave rise to tissue macrophages in all organs of adult birds, and regenerated CSF1-responsive marrow macrophage progenitors. Surprisingly, they did not contribute to any other hematopoietic lineage. To explore the role of CSF1 further, we injected embryonic or hatchling CSF1R-reporter transgenic birds with a novel chicken CSF1-Fc conjugate. In both cases, the treatment produced a large increase in macrophage numbers in all tissues examined. There were no apparent adverse effects of chicken CSF1-Fc on embryonic or post-hatch development, but there was an unexpected increase in bone density in the treated hatchlings. Conclusions: The data indicate that the yolk sac is not the major source of macrophages in adult birds, and that there is a macrophage-restricted, self-renewing progenitor cell in bone marrow. CSF1R is demonstrated to be limiting for macrophage development during development in ovo and post-hatch. The chicken provides a novel and tractable model to study the development of the mononuclear phagocyte system and CSF1R signaling. © Garceau et al.; licensee BioMed Central. | |
2018 |
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Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease (Journal Article) In: PLoS Computational Biology, vol. 14, no. 3, 2018, ISSN: 1553734X, (Publisher: Public Library of Science). | |
Macrophage colony-stimulating factor increases hepatic macrophage content, liver growth, and lipid accumulation in neonatal rats (Journal Article) In: American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 314, no. 3, pp. G388–G398, 2018, ISSN: 01931857, (Publisher: American Physiological Society). | |
The centraliser lattice (Book) Cambridge University Press, 2018, ISBN: 978-1-108-33267-5 978-1-108-41312-1, (Publication Title: New Directions in Locally Compact Groups). | |
Replicable and Coupled Changes in Innate and Adaptive Immune Gene Expression in Two Case-Control Studies of Blood Microarrays in Major Depressive Disorder (Journal Article) In: Biological Psychiatry, vol. 83, no. 1, pp. 70–80, 2018, ISSN: 00063223, (Publisher: Elsevier USA). | |
2017 |
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c-Rel is dispensable for the differentiation and functional maturation of M cells in the follicle-associated epithelium (Journal Article) In: Immunobiology, vol. 222, no. 2, pp. 316–326, 2017, ISSN: 01712985. | |
Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci (Journal Article) In: Cell Reports, vol. 21, no. 11, pp. 3022–3031, 2017, ISSN: 22111247, (Publisher: Elsevier B.V.). | |
The evolution of the macrophage-specific enhancer (Fms intronic regulatory element) within the CSF1R locus of vertebrates (Journal Article) In: Scientific Reports, vol. 7, no. 1, 2017, ISSN: 20452322, (Publisher: Nature Publishing Group). | |
CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus (Journal Article) In: Gut, vol. 66, no. 12, pp. 2098–2109, 2017, ISSN: 00175749, (Publisher: BMJ Publishing Group). | |
Groups with no coarse embeddings into hyperbolic groups (Journal Article) In: New York Journal of Mathematics, vol. 23, pp. 1657–1670, 2017, ISSN: 10769803, (Publisher: University at Albany). | |
Identification of the macrophage-specific promoter signature in FANTOM5 mouse embryo developmental time course data (Journal Article) In: Journal of Leukocyte Biology, vol. 102, no. 4, pp. 1081–1092, 2017, ISSN: 07415400, (Publisher: Federation of American Societies for Experimental Biology). | |
A high resolution atlas of gene expression in the domestic sheep (Ovis aries) (Journal Article) In: PLoS Genetics, vol. 13, no. 9, 2017, ISSN: 15537390, (Publisher: Public Library of Science). | |
Effects of Eimeria tenella infection on chicken caecal microbiome diversity, exploring variation associated with severity of pathology (Journal Article) In: PLoS ONE, vol. 12, no. 9, 2017, ISSN: 19326203, (Publisher: Public Library of Science). | |
FANTOM5 CAGE profiles of human and mouse samples (Journal Article) In: Scientific Data, vol. 4, 2017, ISSN: 20524463, (Publisher: Nature Publishing Groups). | |
The genomic architecture of mastitis resistance in dairy sheep (Journal Article) In: BMC Genomics, vol. 18, no. 1, 2017, ISSN: 14712164, (Publisher: BioMed Central Ltd.). | |
Integration of quantitated expression estimates from polyA-selected and rRNA-depleted RNA-seq libraries (Journal Article) In: BMC Bioinformatics, vol. 18, no. 1, 2017, ISSN: 14712105, (Publisher: BioMed Central Ltd.). | |
Comparative transcriptome analysis of equine alveolar macrophages (Journal Article) In: Equine Veterinary Journal, vol. 49, no. 3, pp. 375–382, 2017, ISSN: 04251644, (Publisher: Equine Veterinary Journal Ltd). | |
Jmjd6, a JmjC dioxygenase with many interaction partners and pleiotropic functions (Journal Article) In: Frontiers in Genetics, vol. 8, no. MAR, 2017, ISSN: 16648021, (Publisher: Frontiers Media S.A.). | |
In: PLoS Genetics, vol. 13, no. 3, 2017, ISSN: 15537390, (Publisher: Public Library of Science). | |
Transcriptional regulation and macrophage differentiation (Book) wiley, 2017, ISBN: 978-1-68367-066-7 978-1-55581-918-7, (Publication Title: Myeloid Cells in Health and Disease: A Synthesis). | |
Stability and the Morse boundary: (Journal Article) In: Journal of the London Mathematical Society, vol. 95, no. 3, pp. 963–988, 2017, ISSN: 00246107, (Publisher: John Wiley and Sons Ltd.). | |
Characterizations of Morse quasi-geodesics via superlinear divergence and sublinear contraction (Journal Article) In: Documenta Mathematica, vol. 22, no. 2017, pp. 1193–1224, 2017, ISSN: 14310635, (Publisher: Deutsche Mathematiker Vereinigung). | |
Transcriptional mechanisms that control expression of the macrophage colony-stimulating factor receptor locus (Journal Article) In: Clinical Science, vol. 131, no. 16, pp. 2161–2182, 2017, ISSN: 01435221, (Publisher: Portland Press Ltd). | |
Embedding mapping class groups into a finite product of trees (Journal Article) In: Groups, Geometry, and Dynamics, vol. 11, no. 2, pp. 613–647, 2017, ISSN: 16617207, (Publisher: European Mathematical Society Publishing House). | |
A continuum of expanders (Journal Article) In: Fundamenta Mathematicae, vol. 238, no. 2, pp. 143–152, 2017, ISSN: 00162736, (Publisher: Instytut Matematyczny). | |
Role of bone marrow macrophages in controlling homeostasis and repair in bone and bone marrow niches (Journal Article) In: Seminars in Cell and Developmental Biology, vol. 61, pp. 12–21, 2017, ISSN: 10849521, (Publisher: Academic Press). | |
Resting and injury-induced inflamed periosteum contain multiple macrophage subsets that are located at sites of bone growth and regeneration (Journal Article) In: Immunology and Cell Biology, vol. 95, no. 1, pp. 7–16, 2017, ISSN: 08189641, (Publisher: Nature Publishing Group). | |
2016 |
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Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility (Journal Article) In: PLOS Pathogens, vol. 12, no. 12, pp. e1006075, 2016, ISSN: 1553-7374. | |
Professor Pete Kaiser 1964-2016 (Journal Article) In: Avian pathology : journal of the W.V.P.A, vol. 45, no. 6, pp. 683–684, 2016, ISSN: 14653338. | |
Analysis of the function of IL-10 in chickens using specific neutralising antibodies and a sensitive capture ELISA (Journal Article) In: Developmental and Comparative Immunology, vol. 63, pp. 206–212, 2016, ISSN: 0145305X, (Publisher: Elsevier Ltd). | |
Genome-wide association studies of immune, disease and production traits in indigenous chicken ecotypes (Journal Article) In: Genetics Selection Evolution, vol. 48, no. 1, 2016, ISSN: 0999193X, (Publisher: BioMed Central Ltd.). | |
A Csf1r-EGFP transgene provides a novel marker for monocyte subsets in sheep (Journal Article) In: Journal of Immunology, vol. 197, no. 6, pp. 2297–2305, 2016, ISSN: 00221767, (Publisher: American Association of Immunologists). | |
Functional annotation of the Ŧ-cell immunoglobulin mucin family in birds (Journal Article) In: Immunology, vol. 148, no. 3, pp. 287–303, 2016, ISSN: 00192805, (Publisher: Blackwell Publishing Ltd). | |
Induction of interferon and cell death in response to cytosolic DNA in chicken macrophages (Journal Article) In: Developmental and Comparative Immunology, vol. 59, pp. 145–152, 2016, ISSN: 0145305X, (Publisher: Elsevier Ltd). | |
Enhancer turnover is associated with a divergent transcriptional response to glucocorticoid in mouse and human macrophages (Journal Article) In: Journal of Immunology, vol. 196, no. 2, pp. 813–822, 2016, ISSN: 00221767, (Publisher: American Association of Immunologists). | |
The genomic architecture of resistance to Campylobacter jejuni intestinal colonisation in chickens (Journal Article) In: BMC Genomics, vol. 17, no. 1, 2016, ISSN: 14712164, (Publisher: BioMed Central Ltd.). | |
Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs (Journal Article) In: American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 311, no. 3, pp. G533–G547, 2016, ISSN: 01931857, (Publisher: American Physiological Society). | |
2015 |
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M Cells (Book Section) In: Ltd, John Wiley Sons (Ed.): eLS, pp. 1–9, John Wiley & Sons, Ltd, Chichester, UK, 2015, ISBN: 978-0-470-01590-2 978-0-470-01617-6. | |
Aging and the mucosal immune system in the intestine (Journal Article) In: Biogerontology, vol. 16, no. 2, pp. 133–145, 2015, ISSN: 1389-5729, 1573-6768. | |
CSF1 Restores Innate Immunity after Liver Injury in Mice and Serum Levels Indicate Outcomes of Patients with Acute Liver Failure (Journal Article) In: Gastroenterology, vol. 149, no. 7, pp. 1896–1909.e14, 2015, ISSN: 00165085, (Publisher: W.B. Saunders). | |
Identification and annotation of conserved promoters and macrophage-expressed genes in the pig genome (Journal Article) In: BMC Genomics, vol. 16, no. 1, 2015, ISSN: 14712164, (Publisher: BioMed Central Ltd.). | |
Third Report on Chicken Genes and Chromosomes 2015: (Journal Article) In: Cytogenetic and Genome Research, vol. 145, no. 2, pp. 78–179, 2015, ISSN: 14248581, (Publisher: S. Karger AG). | |
Immune surveillance of the lung by migrating tissue monocytes (Journal Article) In: eLife, vol. 4, no. JULY 2015, 2015, ISSN: 2050084X, (Publisher: eLife Sciences Publications Ltd). | |
Direct embeddings of relatively hyperbolic groups with optimal ℓp compression exponent (Journal Article) In: Journal fur die Reine und Angewandte Mathematik, vol. 2015, no. 703, pp. 147–172, 2015, ISSN: 00754102, (Publisher: Walter de Gruyter GmbH). | |
Plant breeding: UK bioscientists push for crop policy (Journal Article) In: Nature, vol. 521, no. 7553, pp. 423, 2015, ISSN: 00280836, (Publisher: Nature Publishing Group). | |
Technical advance: Transcription factor, promoter, and enhancer utilization in human myeloid cells (Journal Article) In: Journal of Leukocyte Biology, vol. 97, no. 5, pp. 985–995, 2015, ISSN: 07415400, (Publisher: John Wiley and Sons Inc.). | |
Transcriptional Dynamics Reveal Critical Roles for Non-coding RNAs in the Immediate-Early Response (Journal Article) In: PLoS Computational Biology, vol. 11, no. 4, 2015, ISSN: 1553734X, (Publisher: Public Library of Science). | |
Oncogenic properties of apoptotic tumor cells in aggressive B cell lymphoma (Journal Article) In: Current Biology, vol. 25, no. 5, pp. 577–588, 2015, ISSN: 09609822, (Publisher: Cell Press). | |
Cell-autonomous sex differences in gene expression in chicken bone marrow-derived macrophages (Journal Article) In: Journal of Immunology, vol. 194, no. 5, pp. 2338–2344, 2015, ISSN: 00221767, (Publisher: American Association of Immunologists). | |
Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells (Journal Article) In: Science, vol. 347, no. 6225, pp. 1010–1014, 2015, ISSN: 00368075, (Publisher: American Association for the Advancement of Science). | |
The development and maintenance of the mononuclear phagocyte system of the chick is controlled by signals from the macrophage colony-stimulating factor receptor (Journal Article) In: BMC Biology, vol. 13, no. 1, 2015, ISSN: 17417007, (Publisher: BioMed Central Ltd.). | |