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

Das, Sadhan; Senapati, Parijat; Chen, Zhuo; Reddy, Marpadga A.; Ganguly, Rituparna; Lanting, Linda; Mandi, Varun; Bansal, Anita; Leung, Amy; Zhang, Selena; Jia, Yong; Wu, Xiwei; Schones, Dustin E.; Natarajan, Rama

doi:10.1038/s41467-017-01629-7

Cited by 82 publications

(85 citation statements)

References 69 publications

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“…H1299 cells were maintained in RPMI‐1640 supplemented with 10% FBS up to 80% confluency. ChIP experiments were performed as described previously . Briefly, 10–15 million cells seeded in 100 mm dishes were cross‐linked using 1% formaldehyde, followed by cell lysis in SDS lysis buffer [1% SDS, 10 m m ethylenediaminetetraacetic acid (EDTA), 50 m m Tris–HCl, pH 8] and subjected to sonication using a Diagenode Bioruptor (Leige, Belgium) to produce DNA fragments of 100–300 bp in length using cold ChIP‐dilution buffer (0.01% SDS, 1.1% Triton X‐100, 1.2 m m EDTA, 16.7 m m Tris‐HCl, pH 8, 167 m m NaCl).…”

Section: Methodsmentioning

confidence: 99%

Oncogene c‐fos and mutant R175H p53 regulate expression of Nucleophosmin implicating cancer manifestation

et al. 2018

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Nucleophosmin (NPM1) is a nucleolar protein that is frequently overexpressed in various types of solid tumors. NPM1 is involved in several cellular processes that might contribute significantly to the increased proliferation potential of cancers. Previous reports suggest that NPM1 expression is highly increased in response to mitogenic and oncogenic signals, the mechanisms of which have not been elucidated extensively. Using constructs incorporating different fragments of the NPM1 promoter upstream to a Luciferase reporter gene, we have identified the minimal promoter of NPM1 and candidate transcription factors regulating NPM1 promoter activity by luciferase reporter assays. We have validated the roles of a few candidate factors at the transcriptional and protein level by quantitative reverse transcriptase PCR, immunoblotting and immunohistochemistry, and explored the mechanism of regulation of NPM1 expression using immunoprecipitation and chromatin immunoprecipitation assays. We show here that the expression of NPM1 is regulated by transcription factor c-fos, a protein that is strongly activated by growth factor signals. In addition, mutant p53 (R175H) overexpression also enhances NPM1 expression possibly through c-myc and c-fos. Moreover, both c-fos and mutant p53 are overexpressed in oral tumor tissues that showed NPM1 overexpression. Collectively, our results suggest that c-fos and mutant p53 R175H positively regulate NPM1 expression, possibly in synergism, that might lead to oncogenic manifestation.

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Section: Methodsmentioning

confidence: 99%

Oncogene c‐fos and mutant R175H p53 regulate expression of Nucleophosmin implicating cancer manifestation

et al. 2018

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“…As mentioned, bioinformatic analysis has been used to identify lncRNAs associated with hypertension and ANG II stimulation of VSMCs (1108). Genome-wide Chipseq analysis identified over 2,000 enhancers regulated by ANG II in VSMCs (206). In addition, unbiased gene screening approaches have been employed to explore ANG II signal transduction.…”

Section: F System Biology and Bioinformaticsmentioning

confidence: 99%

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Forrester

Booz

Sigmund

et al. 2018

Physiological Reviews

816

780

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The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (ATR) is believed to mediate most functions of ANG II in the system. ATR utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between ATR signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. ATR remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.

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“…An interesting study investigated the regulation of the angiotensin II (AngII) response by enhancers in vascular smooth muscle cells (VSMCs; 24). They performed ChIP-Seq to identify changes in enhancer activity and found thousands of changes in H3K27Ac occupancy in cells treated with AngII.…”

Section: Normal Physiology and Diseasementioning

confidence: 99%

“…From that, they discovered that genes proximal to these enhancers had promoters with increased H3K27Ac. Additionally, RNA-seq data showed these genes were upregulated significantly more compared to upregulated genes not associated with an enhancer (24). This study provides a model in which epigenetic changes allow enhancers to help facilitate the large scale, downstream response to Angiotensin II in vascular smooth muscle cells.…”

Section: Normal Physiology and Diseasementioning

confidence: 99%

Genome‐Wide Maps of Transcription Regulatory Elements and Transcription Enhancers in Development and Disease

Agrawal

Heimbruch

Rao

2018

Comprehensive Physiology

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Gene expression is regulated by numerous elements including enhancers, insulators, transcription factors, and architectural proteins. Regions of DNA distal to the transcriptional start site, called enhancers, play a central role in the temporal and tissue-specific regulation of gene expression through RNA polymerase II. The identification of enhancers and other cis regulatory elements has largely been possible due to advances in next generation sequencing technologies. Enhancers regulate gene expression through chromatin loops mediated by architectural proteins such as YY1, CTCF, the cohesin complex, and LDB1. Additionally, enhancers can be transcribed to produce non-coding RNAs termed enhancer RNAs that likely participate in transcriptional regulation. The central role of enhancers in regulating gene expression implicates them in both normal physiology but also many disease states. The importance of enhancers is evident by the suggested role of SNPs, duplications, and other alterations of enhancer function in many diseases, ranging from cancer to atherosclerosis to chronic kidney disease. Although much progress has been made in recent years, the field of enhancer biology and our knowledge of the cis regulome remains a work in progress. This review will highlight recent seminal studies which demonstrate the role of enhancers in normal physiology and disease pathogenesis.

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

Cited by 82 publications

References 69 publications

Oncogene c‐fos and mutant R175H p53 regulate expression of Nucleophosmin implicating cancer manifestation

Oncogene c‐fos and mutant R175H p53 regulate expression of Nucleophosmin implicating cancer manifestation

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

Genome‐Wide Maps of Transcription Regulatory Elements and Transcription Enhancers in Development and Disease

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