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A transcriptional switch governs fibroblast activation in heart disease

机译：转录切换治理心脏病中的成纤维细胞活化

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摘要

In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that 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 inhibitors to 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 TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-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.
机译：在患病器官中，应激激活的信号传导级联改变染色质，从而触发不良细胞状态过渡。成纤维细胞活化是一种肺，肝，肾和心脏病的组织中的常见应激反应，但其机械基础仍然不清楚〜（1,2）。药理抑制溴琼瘤和外末端域（BET）蛋白减轻了心脏功能障碍〜（3-7），提供了一种询问和调节心电池状态作为潜在治疗方法的工具。在这里，我们使用动态地暴露于Bet抑制剂的单细胞外形分析，以揭示底层激活成纤维细胞的可逆转录开关。常规心脏成纤维细胞以与BET抑制剂暴露和心脏功能直接相关的方式稳健地在静态和活化状态之间切换。单细胞染色质无障碍揭示了先前未描述的DNA元件，其可访问性与心脏能动态相关。在最动态的元素中是调节转录因子Meox1的增强子，其在活性成纤维细胞中特异性表达，占据宽纤维化基因计划的推定调节元件，并且是TGFβ诱导的成纤维细胞活化所必需的。选择性CRISPR抑制增强子内的单一动态CIS-元素抑制TGFβ诱导的MEOX1活化。我们鉴定Meox1作为与心脏功能障碍相关的成纤维细胞活化的中央调节因子，并在激活人肺，肝肾成纤维细胞后证明其上调。组织成纤维细胞中BET依赖性调节的可塑性和特异性提供了用于治疗纤维化疾病的先前未知的转斜肌和顺式靶标。

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  • 来源
    《Nature》 |2021年第7867期|438-443|共6页
  • 作者

    Michael Alexanian; Pawel F Przytycki; Rudi Micheletti; Arun Padmanabhan; Lin Ye; Joshua G Travers; Barbara Gonzalez-Teran; Ana Catarina Silva; Qiming Duan; Sanjeev S Ranade; Franco Felix; Ricardo Linares-Saldana; Li Li; Clara Youngna Lee; Nandhini Sadagopan; Angelo Pelonero; Yu Huang; Gaia Andreoletti; Rajan Jain; Timothy A McKinsey; Michael G Rosenfeld; Casey A Gifford; Katherine S Pollard; Saptarsi M Haldar; Deepak Srivastava;

  • 作者单位

    Gladstone Institutes;

    Gladstone Institutes;

    Howard Hughes Medical Institute Department and School of Medicine University of California;

    Gladstone Institutes|Department of Medicine Cardiology Division UCSF School of Medicine;

    Gladstone Institutes;

    Department of Medicine Division of Cardiology and Consortium for Fibrosis Research & Translation University of Colorado Anschutz Medical Campus;

    Gladstone Institutes;

    Gladstone Institutes;

    Gladstone Institutes;

    Gladstone Institutes;

    Gladstone Institutes;

    Cardiovascular Institute and Department of Medicine Perelman School of Medicine University of Pennsylvania;

    Cardiovascular Institute and Department of Medicine Perelman School of Medicine University of Pennsylvania;

    Gladstone Institutes;

    Gladstone Institutes|Department of Medicine Cardiology Division UCSF School of Medicine;

    Gladstone Institutes;

    Gladstone Institutes;

    Institute for Computational Health Sciences University of California;

    Cardiovascular Institute and Department of Medicine Perelman School of Medicine University of Pennsylvania;

    Department of Medicine Division of Cardiology and Consortium for Fibrosis Research & Translation University of Colorado Anschutz Medical Campus;

    Howard Hughes Medical Institute Department and School of Medicine University of California;

    Gladstone Institutes;

    Gladstone Institutes|Institute for Computational Health Sciences University of California|Chan-Zuckerberg Biohub|Department of Epidemiology & Biostatistics University of California|Institute for Human Genetics University of California;

    Gladstone Institutes|Department of Medicine Cardiology Division UCSF School of Medicine|Amgen Research Cardiometabolic Disorders;

    Gladstone Institutes|Department of Pediatrics UCSF School of Medicine|Roddenberry Center for Stem Cell Biology and Medicine at Gladstone|Department of Biochemistry and Biophysics University of California;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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