Dual roles of chromatin remodeling protein BRG1 in angiotensin II-induced endothelial–mesenchymal transition
Open Access
- 18 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (7), 1-14
- https://doi.org/10.1038/s41419-020-02744-y
Abstract
Endothelial–mesenchymal transition (EndMT) is considered one of the processes underlying tissue fibrosis by contributing to the pool of myofibroblasts. In the present study, we investigated the epigenetic mechanism whereby angiotensin II (Ang II) regulates EndMT to promote cardiac fibrosis focusing on the role of chromatin remodeling protein BRG1. BRG1 knockdown or inhibition attenuated Ang II-induced EndMT, as evidenced by down-regulation of CDH5, an endothelial marker, and up-regulation of COL1A2, a mesenchymal marker, in cultured vascular endothelial cells. On the one hand, BRG1 interacted with and was recruited by Sp1 to the SNAI2 (encoding SLUG) promoter to activate SNAI2 transcription in response to Ang II stimulation. Once activated, SLUG bound to the CDH5 promoter to repress CDH5 transcription. On the other hand, BRG1 interacted with and was recruited by SRF to the COL1A2 promoter to activate COL1A2 transcription. Mechanistically, BRG1 evicted histones from the target promoters to facilitate the bindings of Sp1 and SRF. Finally, endothelial conditional BRG1 knockout mice (CKO) exhibited a reduction in cardiac fibrosis, compared to the wild type (WT) littermates, in response to chronic Ang II infusion. In conclusion, our data demonstrate that BRG1 is a key transcriptional coordinator programming Ang II-induced EndMT to contribute to cardiac fibrosis.Funding Information
- National Natural Science Foundation of China (81725001)
This publication has 73 references indexed in Scilit:
- Megakaryocytic leukemia 1 (MKL1) ties the epigenetic machinery to hypoxia-induced transactivation of endothelin-1Nucleic Acids Research, 2013
- Myocardin-related Transcription Factor-A Complexes Activate Type I Collagen Expression in Lung Fibroblasts*Journal of Biological Chemistry, 2011
- Regulation of endothelial cell plasticity by TGF-βCell and tissue research, 2011
- Chromatin regulation by Brg1 underlies heart muscle development and diseaseNature, 2010
- ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1Oncogene, 2010
- Hypoxic Repression of Endothelial Nitric-oxide Synthase Transcription Is Coupled with Eviction of Promoter HistonesOnline Journal of Public Health Informatics, 2010
- Myocardial remodeling after infarction: the role of myofibroblastsNature Reviews Cardiology, 2009
- Transforming Growth Factor-β1 Represses E-Cadherin Production viaSlugExpression in Lens Epithelial CellsInvestigative Ophthalmology & Visual Science, 2007
- Inhibition of Transforming Growth Factor β-enhanced Serum Response Factor-dependent Transcription by SMAD7Online Journal of Public Health Informatics, 2006
- Angiotensin II Regulation of Collagen Type I Expression in Cardiac FibroblastsHypertension, 2004