Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
Molecular Medicine Unit, UCL Institute of Child Health, London WC1N 1EH, UK.
Nat Commun. 2017 Jul 24;8:16034. doi: 10.1038/ncomms16034.
Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin β4 (Tβ4) and myocardial infarction (MI) by reactivating a fetal gene programme to promote neovascularization and cardiomyogenesis. The mechanism for epicardial gene (re-)activation remains elusive. Here we reveal that BRG1, the essential ATPase subunit of the SWI/SNF chromatin-remodelling complex, is required for expression of Wilms' tumour 1 (Wt1), fetal EPDC activation and subsequent differentiation into coronary smooth muscle, and restores Wt1 activity upon MI. BRG1 physically interacts with Tβ4 and is recruited by CCAAT/enhancer-binding protein β (C/EBPβ) to discrete regulatory elements in the Wt1 locus. BRG1-Tβ4 co-operative binding promotes optimal transcription of Wt1 as the master regulator of embryonic EPDCs. Moreover, chromatin immunoprecipitation-sequencing reveals BRG1 binding at further key loci suggesting SWI/SNF activity across the fetal epicardial gene programme. These findings reveal essential functions for chromatin-remodelling in the activation of EPDCs during cardiovascular development and repair.
心外膜细胞（EPDCs）在发育过程中贡献心血管细胞类型，并在成年后通过重新激活胎儿基因程序来响应胸腺素β4（Tβ4）和心肌梗死（MI），从而促进血管新生和心肌发生。心外膜基因（重新）激活的机制仍不清楚。在这里，我们揭示了 BRG1 是 SWI/SNF 染色质重塑复合物的必需 ATP 酶亚基，对于 Wilms 瘤 1（Wt1）的表达、胎儿 EPDC 的激活以及随后分化为冠状动脉平滑肌是必需的，并在 MI 后恢复 Wt1 活性。BRG1 与 Tβ4 相互作用，并被 CCAAT/增强子结合蛋白β（C/EBPβ）募集到 Wt1 基因座中的离散调节元件。BRG1-Tβ4 合作结合促进了 Wt1 的最佳转录，作为胚胎 EPDC 的主调控因子。此外，染色质免疫沉淀测序显示 BRG1 在进一步的关键基因座上结合，提示 SWI/SNF 活性跨越胎儿心外膜基因程序。这些发现揭示了染色质重塑在心血管发育和修复过程中 EPDC 激活中的重要功能。
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