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Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells.


ABSTRACT: Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. AngII-induced enhancers/SEs are enriched in binding sites for signal-dependent transcription factors and dependent on key signaling kinases. Moreover, CRISPR-Cas9-mediated deletion of candidate enhancers/SEs, targeting SEs with the bromodomain and extra-terminal domain inhibitor JQ1, or knockdown of overlapping long noncoding RNAs (lncRNAs) blocks AngII-induced genes associated with growth-factor signaling and atherosclerosis. Furthermore, JQ1 ameliorates AngII-induced hypertension, medial hypertrophy and inflammation in vivo in mice. These results demonstrate AngII-induced signals integrate enhancers/SEs and lncRNAs to increase expression of genes involved in VSMC dysfunction, and could uncover novel therapies.

SUBMITTER: Das S 

PROVIDER: S-EPMC5684340 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells.

Das Sadhan S   Senapati Parijat P   Chen Zhuo Z   Reddy Marpadga A MA   Ganguly Rituparna R   Lanting Linda L   Mandi Varun V   Bansal Anita A   Leung Amy A   Zhang Selena S   Jia Ye Y   Wu Xiwei X   Schones Dustin E DE   Natarajan Rama R  

Nature communications 20171113 1


Angiotensin II (AngII) promotes hypertension and atherosclerosis by activating growth-promoting and pro-inflammatory gene expression in vascular smooth muscle cells (VSMCs). Enhancers and super-enhancers (SEs) play critical roles in driving disease-associated gene expression. However, enhancers/SEs mediating VSMC dysfunction remain uncharacterized. Here, we show that AngII alters vascular enhancer and SE repertoires in cultured VSMCs in vitro, ex vivo, and in AngII-infused mice aortas in vivo. A  ...[more]

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