A disease-associated gene desert directs macrophage inflammation through ETS2
成果类型：
Article
署名作者：
Stankey, C. T.; Bourges, C.; Haag, L. M.; Turner-Stokes, T.; Piedade, A. P.; Palmer-Jones, C.; Papa, I.; dos Santos, M. Silva; Zhang, Q.; Cameron, A. J.; Legrini, A.; Zhang, T.; Wood, C. S.; New, F. N.; Randzavola, L. O.; Speidel, L.; Brown, A. C.; Hall, A.; Saffioti, F.; Parkes, E. C.; Edwards, W.; Direskeneli, H.; Grayson, P. C.; Jiang, L.; Merkel, P. A.; Saruhan-Direskeneli, G.; Sawalha, A. H.; Tombetti, E.; Quaglia, A.; Thorburn, D.; Knight, J. C.; Rochford, A. P.; Murray, C. D.; Divakar, P.; Green, M.; Nye, E.; MacRae, J. I.; Jamieson, N. B.; Skoglund, P.; Cader, M. Z.; Wallace, C.; Thomas, D. C.; Lee, J. C.
署名单位：
Francis Crick Institute; Imperial College London; Washington University (WUSTL); Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; University of London; University College London; UCL Medical School; Royal Free London NHS Foundation Trust; University of London; University College London; Francis Crick Institute; Wellcome Trust Sanger Institute; University of Glasgow; NanoString Technologies; Francis Crick Institute; University of London; University College London; University of Oxford; Wellcome Centre for Human Genetics; University of London; University College London; Royal Free London NHS Foundation Trust; UCL Medical School; University of London; University College London; UCL Medical School; Royal Free London NHS Foundation Trust; University of Cambridge; Marmara University; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS); Fudan University; University of Pennsylvania; University of Pennsylvania; Istanbul University; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of Milan; University of London; University College London; University of Oxford; Francis Crick Institute; University of Cambridge; University of Cambridge; MRC Biostatistics Unit
刊物名称：
Nature
ISSN/ISSBN：
0028-5689
DOI：
10.1038/s41586-024-07501-1
发表日期：
2024-07-13
页码：
447-+
关键词：
coverage neanderthal genome
transcription factor
susceptibility loci
takayasu arteritis
wide association
sequence
expression
identification
enhancers
differentiation
摘要：
Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health(1). This is compounded by the limited efficacy of available treatments(1) and high failure rates during drug development(2), highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis(3-6)-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures(7), we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.