期刊
NATURE
卷 595, 期 7867, 页码 438-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03674-1
关键词
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资金
- Swiss National Science Foundation [P400PM_186704, P2LAP3_178056]
- NIH [P01 HL098707, HL098179, R01 AG070154, K08HL157700, F32 HL147463, R01 HL116848, R01 HL147558, R01 DK119594, R01 HL150225, R01 HL127240, P01 HL146366, R01 HL057181, R01 HL015100, R01 HL150521]
- Tobacco-Related Disease Research Program [578649]
- A. P. Giannini Foundation [P0527061]
- Michael Antonov Charitable Foundation
- Sarnoff Cardiovascular Research foundation
- American Heart Association [16SFRN31400013, 18POST34080175]
- Burroughs Wellcome Fund
- Allen Foundation
- HHMI
- Roddenberry Foundation
- L.K. Whittier Foundation
- Younger Family Fund
- NIH/NCRR [C06 RR018928]
- Gladstone Institutes
- San Simeon Fund
- American Heart Association
- Swiss National Science Foundation (SNF) [P400PM_186704, P2LAP3_178056] Funding Source: Swiss National Science Foundation (SNF)
In diseased organs, stress-activated signalling cascades alter chromatin, triggering maladaptive cell state transitions. Inhibition of BET proteins alleviates cardiac dysfunction and reveals a reversible transcriptional switch in fibroblasts. This study identifies MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction, providing potential targets for treating fibrotic disease.
In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissuesthat worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear(1,2). Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction(3-7), providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use single-cell epigenomic analyses of hearts dynamically exposed to BET inhibitorsto reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGF beta-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGF beta-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans- and cis-targets for treating fibrotic disease.
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