小柯机器人

转录开关调控心脏成纤维细胞活化
2021-06-27 15:48

美国格莱斯顿研究所Deepak Srivastava、Saptarsi M. Haldar课题组合作的研究发现在心脏病患者中,转录开关控制成纤维细胞活化。相关论文发表在2021年6月23日出版的《自然》杂志上。

在本研究中,研究人员利用单细胞表观基因组分析探究了用溴结构域和末端外结构域 (BET)抑制剂动态处理心脏细胞的可逆转录转换,其是成纤维细胞激活的基础。常驻心脏成纤维细胞以与 BET 抑制剂结合和心脏功能直接相关的方式表现出静止和激活状态间的快速切换。单细胞染色质可及性揭示了以前未知的 DNA元件,其可及性与心脏功能动态相关。

其中最具活力的元件是调节转录因子MEOX1的增强子,它在活化的成纤维细胞中特异性表达,是广泛纤维化基因程序的假定调节元件,并且是TGFβ诱导成纤维细胞活化所必需的。选择性CRISPR抑制增强子中单个最具活力的顺式元件可阻断TGFβ诱导的Meox1激活。研究认为MEOX1是与心功能障碍相关成纤维细胞活化的中枢调节因子,并证明其在人肺、肝和肾成纤维细胞活化后上调。组织成纤维细胞中MEOX1 BET依赖性调节可塑性和特异性为治疗纤维化疾病提供了先前未知的反式和顺式靶点。

据悉,在病灶器官中,应激激活的信号级联反应会改变染质,从而产生适宜疾病的细胞状态转变。成纤维细胞激活是组织中常见的应激反应,可导致肺、肝、肾和心脏病恶化,但其致病机制仍不清楚。药物抑制BET蛋白可减轻心脏功能障碍,这提供了一种整合和调节心脏细胞状态的方法,是一种潜在的治疗手段。

附:英文原文

Title: A transcriptional switch governs fibroblast activation in heart disease

Author: 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

Issue&Volume: 2021-06-23

Abstract: 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 unclear1,2. Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction3,4,5,6,7, 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.

DOI: 10.1038/s41586-021-03674-1

Source: https://www.nature.com/articles/s41586-021-03674-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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