Regulation of Angiotensin II Actions by Enhancers and Super-enhancers in Vascular Smooth Muscle Cells

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Nov 15

PMID 29133788

Citations 50

Authors

Sadhan Das

Parijat Senapati

Zhuo Chen

Marpadga A Reddy

Rituparna Ganguly

Linda Lanting

Varun Mandi

Anita Bansal

Amy Leung

Selena Zhang

Ye Jia

Xiwei Wu

Dustin E Schones

Rama Natarajan

Affiliations

Soon will be listed here.

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.

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