Regulation of angiotensin II actions by enhancers and super-enhancers in vascular smooth muscle cells
| Autor: | Zhuo Chen, Marpadga A. Reddy, Rituparna Ganguly, Parijat Senapati, Rama Natarajan, Varun Mandi, Sadhan Das, Anita Bansal, Amy Leung, Linda Lanting, Dustin E. Schones, Selena Zhang, Xiwei Wu, Ye Jia |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Angiotensin receptor Vascular smooth muscle Science Myocytes Smooth Muscle General Physics and Astronomy 030204 cardiovascular system & hematology Biology Article Muscle Smooth Vascular General Biochemistry Genetics and Molecular Biology Histones Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Gene expression Animals lcsh:Science Enhancer Transcription factor Aorta Cells Cultured Regulation of gene expression Gene knockdown Multidisciplinary Angiotensin II Azepines General Chemistry Triazoles Atherosclerosis Rats Cell biology Mice Inbred C57BL 030104 developmental biology Gene Expression Regulation Hypertension cardiovascular system lcsh:Q RNA Long Noncoding hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Nature Communications, Vol 8, Iss 1, Pp 1-19 (2017) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. The repertoire of tissue-specific distal regulators of gene transcription enhancers defines homeostasis or disease. Here, the authors reveal the enhancer and super-enhancer signature of vascular smooth muscle cells under normal and angiotensin II stimuli, providing new insight into the transcriptional regulation of vascular pathologies. |
| Databáze: | OpenAIRE |
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