Publication: A disease-associated gene desert directs macrophage inflammation through ETS2
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Date
2024-06-13
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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.
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Temel Bilimler, Natural Sciences, Temel Bilimler (SCI), Doğa Bilimleri Genel, ÇOK DİSİPLİNLİ BİLİMLER, Natural Sciences (SCI), NATURAL SCIENCES, GENERAL, MULTIDISCIPLINARY SCIENCES, Multidisipliner, Multidisciplinary
Citation
Stankey C., Bourges C., Haag L., Turner-Stokes T., Piedade A., Palmer-Jones C., Papa I., Silva dos Santos M., Zhang Q., Cameron A., et al., "A disease-associated gene desert directs macrophage inflammation through ETS2", Nature, cilt.630, sa.8016, ss.447-456, 2024