期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms16034
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资金
- British Heart Foundation [RG/08/003/25264]
- BHF Oxbridge Regenerative Medicine Centre [RM/13/3/30159]
- British Heart Foundation [RG/13/9/30269, RG/08/003/25264] Funding Source: researchfish
- Medical Research Council [G0902418] Funding Source: researchfish
- MRC [G0902418] Funding Source: UKRI
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.
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