A disease-associated gene desert directs macrophage inflammation through ETS2.

Autor: Stankey CT; Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK.; Department of Immunology and Inflammation, Imperial College London, London, UK.; Washington University School of Medicine, St Louis, MO, USA., Bourges C; Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK., Haag LM; Division of Gastroenterology, Infectious Diseases and Rheumatology, Charité-Universitätsmedizin Berlin, Berlin, Germany., Turner-Stokes T; Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK.; Department of Immunology and Inflammation, Imperial College London, London, UK., Piedade AP; Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK., Palmer-Jones C; Department of Gastroenterology, Royal Free Hospital, London, UK.; Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK., Papa I; Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK., Silva Dos Santos M; Metabolomics STP, The Francis Crick Institute, London, UK., Zhang Q; Genomics of Inflammation and Immunity Group, Human Genetics Programme, Wellcome Sanger Institute, Hinxton, UK., Cameron AJ; Wolfson Wohl Cancer Centre, School of Cancer Sciences, University of Glasgow, Glasgow, UK., Legrini A; Wolfson Wohl Cancer Centre, School of Cancer Sciences, University of Glasgow, Glasgow, UK., Zhang T; Wolfson Wohl Cancer Centre, School of Cancer Sciences, University of Glasgow, Glasgow, UK., Wood CS; Wolfson Wohl Cancer Centre, School of Cancer Sciences, University of Glasgow, Glasgow, UK., New FN; NanoString Technologies, Seattle, WA, USA., Randzavola LO; Department of Immunology and Inflammation, Imperial College London, London, UK., Speidel L; Ancient Genomics Laboratory, The Francis Crick Institute, London, UK.; Genetics Institute, University College London, London, UK., Brown AC; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK., Hall A; The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK.; Department of Cellular Pathology, Royal Free Hospital, London, UK., Saffioti F; Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK.; The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK., Parkes EC; Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK., Edwards W; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK., Direskeneli H; Department of Internal Medicine, Division of Rheumatology, Marmara University, Istanbul, Turkey., Grayson PC; Systemic Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, MD, USA., Jiang L; Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China., Merkel PA; Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Division of Epidemiology, Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, USA., Saruhan-Direskeneli G; Department of Physiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey., Sawalha AH; Division of Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.; Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.; Lupus Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA.; Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA., Tombetti E; Department of Biomedical and Clinical Sciences, Milan University, Milan, Italy.; Internal Medicine and Rheumatology, ASST FBF-Sacco, Milan, Italy., Quaglia A; Department of Cellular Pathology, Royal Free Hospital, London, UK.; UCL Cancer Institute, London, UK., Thorburn D; Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK.; The Sheila Sherlock Liver Centre, Royal Free Hospital, London, UK., Knight JC; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.; Chinese Academy of Medical Sciences Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.; NIHR Comprehensive Biomedical Research Centre, Oxford, UK., Rochford AP; Department of Gastroenterology, Royal Free Hospital, London, UK.; Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK., Murray CD; Department of Gastroenterology, Royal Free Hospital, London, UK.; Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK., Divakar P; NanoString Technologies, Seattle, WA, USA., Green M; Experimental Histopathology STP, The Francis Crick Institute, London, UK., Nye E; Experimental Histopathology STP, The Francis Crick Institute, London, UK., MacRae JI; Metabolomics STP, The Francis Crick Institute, London, UK., Jamieson NB; Wolfson Wohl Cancer Centre, School of Cancer Sciences, University of Glasgow, Glasgow, UK., Skoglund P; Ancient Genomics Laboratory, The Francis Crick Institute, London, UK., Cader MZ; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Wallace C; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.; MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, UK., Thomas DC; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.; Department of Medicine, University of Cambridge, Cambridge, UK., Lee JC; Genetic Mechanisms of Disease Laboratory, The Francis Crick Institute, London, UK. james.lee@crick.ac.uk.; Department of Gastroenterology, Royal Free Hospital, London, UK. james.lee@crick.ac.uk.; Institute for Liver and Digestive Health, Division of Medicine, University College London, London, UK. james.lee@crick.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Jun; Vol. 630 (8016), pp. 447-456. Date of Electronic Publication: 2024 Jun 05.
DOI: 10.1038/s41586-024-07501-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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