BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease

作者：Vieira Joaquim Miguel; Howard Sara; del Campo Cristina Villa; Bollini Sveva; Dube Karina N; Masters Megan; Barnette Damien N; Rohling Mala; Sun Xin; Hankins Laura E; Gavriouchkina Daria; Williams Ruth; Metzger Daniel; Chambon Pierre; Sauka Spengler Tatjana; Davies Benjamin; Riley Paul R^*

来源：Nature Communications, 2017, 8(1): 16034.

DOI：10.1038/ncomms16034

Epicardium-derived cells (EPDCs) contribute cardiovascular cell types during development and in adulthood respond to Thymosin beta 4 (T beta 4) 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 T beta 4 and is recruited by CCAAT/enhancer-binding protein beta (C/EBP beta) to discrete regulatory elements in the Wt1 locus. BRG1-T beta 4 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.

• 出版日期2017-7-24