A disease-associated gene desert directs macrophage inflammation through ETS2
C. T. Stankey,
C. Bourges,
L. M. Haag,
T. Turner-Stokes,
A. P. Piedade,
C. Palmer-Jones,
I. Papa,
M. Silva dos Santos,
Q. Zhang,
A. J. Cameron,
A. Legrini,
T. Zhang,
C. S. Wood,
F. N. New,
L. O. Randzavola,
L. Speidel,
A. C. Brown,
A. Hall,
F. Saffioti,
E. C. Parkes,
W. Edwards,
H. Direskeneli,
P. C. Grayson,
L. Jiang,
P. A. Merkel,
G. Saruhan-Direskeneli,
A. H. Sawalha,
E. Tombetti,
A. Quaglia,
D. Thorburn,
J. C. Knight,
A. P. Rochford,
C. D. Murray,
P. Divakar,
M. Green,
E. Nye,
J. I. MacRae,
N. B. Jamieson,
P. Skoglund,
M. Z. Cader,
C. Wallace,
D. C. Thomas and
J. C. Lee ()
Additional contact information
C. T. Stankey: The Francis Crick Institute
C. Bourges: The Francis Crick Institute
L. M. Haag: Charité–Universitätsmedizin Berlin
T. Turner-Stokes: The Francis Crick Institute
A. P. Piedade: The Francis Crick Institute
C. Palmer-Jones: Royal Free Hospital
I. Papa: The Francis Crick Institute
M. Silva dos Santos: The Francis Crick Institute
Q. Zhang: Wellcome Sanger Institute
A. J. Cameron: University of Glasgow
A. Legrini: University of Glasgow
T. Zhang: University of Glasgow
C. S. Wood: University of Glasgow
F. N. New: NanoString Technologies
L. O. Randzavola: Imperial College London
L. Speidel: The Francis Crick Institute
A. C. Brown: University of Oxford
A. Hall: Royal Free Hospital
F. Saffioti: University College London
E. C. Parkes: The Francis Crick Institute
W. Edwards: University of Cambridge
H. Direskeneli: Marmara University
P. C. Grayson: National Institutes of Health
L. Jiang: Fudan University
P. A. Merkel: University of Pennsylvania
G. Saruhan-Direskeneli: Istanbul Faculty of Medicine
A. H. Sawalha: University of Pittsburgh
E. Tombetti: Milan University
A. Quaglia: Royal Free Hospital
D. Thorburn: University College London
J. C. Knight: University of Oxford
A. P. Rochford: Royal Free Hospital
C. D. Murray: Royal Free Hospital
P. Divakar: NanoString Technologies
M. Green: The Francis Crick Institute
E. Nye: The Francis Crick Institute
J. I. MacRae: The Francis Crick Institute
N. B. Jamieson: University of Glasgow
P. Skoglund: The Francis Crick Institute
M. Z. Cader: University of Cambridge
C. Wallace: University of Cambridge
D. C. Thomas: University of Cambridge
J. C. Lee: The Francis Crick Institute
Nature, 2024, vol. 630, issue 8016, 447-456
Abstract:
Abstract Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, 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 arteritis3–6—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 signatures7, 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.
Date: 2024
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DOI: 10.1038/s41586-024-07501-1
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