Epigenetic regulation of endothelial‐cell‐mediated vascular repair

Fraineau, Sylvain; Palii, Carmen G.; Allan, David S.; Brand, Marjorie

doi:10.1111/febs.13183

Cited by 69 publications

(51 citation statements)

References 175 publications

(398 reference statements)

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“…The epigenetic control of EC biology, however, is incompletely understood. [2][3][4] Histone methylation is an important mechanism of epigenetic regulation. Trimethylation at histone 3 lysine 4 (H3K4me3), located in promoter regions, is associated with gene expression.…”

mentioning

confidence: 99%

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Fork

Hitzel

et al. 2015

ATVB

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Objective-Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. Approach and Results-To identify chromatin modifying enzymes in endothelial cells, histone demethylases were screened by microarray and polymerase chain reaction. The histone 3 lysine 4 demethylase JARID1B was identified as a highly expressed enzyme at the mRNA and protein levels. Knockdown of JARID1B by shRNA in human umbilical vein endothelial cells attenuated cell migration, angiogenic sprouting, and tube formation. Similarly, pharmacological inhibition and overexpression of a catalytic inactive JARID1B mutant reduced the angiogenic capacity of human umbilical vein endothelial cells. To identify the in vivo relevance of JARID1B in the vascular system, Jarid1b knockout mice were studied. As global knockout results in increased mortality and developmental defects, tamoxifen-inducible and endothelial-specific knockout mice were generated. Acute knockout of Jarid1b attenuated retinal angiogenesis and endothelial sprout outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C, induced HOXA5 expression in human umbilical vein endothelial cells. Consistently, chromatin immunoprecipitation revealed that JARID1B occupies and reduces the histone 3 lysine 4 methylation levels at the HOXA5 promoter, demonstrating a direct function of JARID1B in endothelial HOXA5 gene regulation. Conclusions-JARID1B, by suppressing HOXA5, maintains the endothelial angiogenic capacity in a demethylasedependent manner.

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confidence: 99%

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Fork

Hitzel

et al. 2015

ATVB

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“…These alterations include the post-translational addition or removal of methyl groups to DNA as well as methyl, acetyl, sumoyl and phospho groups to histones and other kind of proteins. These changes participate in remodelling chromatin and modifying its accessibility to transcription factors and cofactors [17]. Epigenetic control is one of the main regulatory systems contributing to phenotypic diferences between cell types in multicellular organisms.…”

Section: Epigeneticsmentioning

confidence: 99%

“…The acetylation status of histone is ine-tuned by histone acetyltransferases (HATs) and HDACs. HDACs are enzymes that remove acetyl groups from histone lysine residues thereby increasing their negative charges, which lead to chromatin condensation and gene repression [17].…”

Section: Histone Modiicationmentioning

confidence: 99%

Angiogenesis and Cardiovascular Diseases: The Emerging Role of HDACs

Moraga¹,

Lao²,

Zeng³

2017

Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

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Cardiovascular diseases (CVD) continue to be the leading cause of death in the world despite recent therapeutic advances. Although many CVDs remain incurable, enormous eforts have been placed in harnessing angiogenesis as therapeutics for these diseases. Epigenetics, the modiication of gene expression post-transcriptionally and post-translationally, are important in regulating many biological processes. One of the main post-translational epigenetic modiications, modiication of chromatin structure by the acetylation of histone tails within the chromatin by either histone deacetylases (HDACs) or histone acetyltransferases (HATs), is important in modulating gene transcription and has emerged as an important regulatory player from pathogenesis to therapeutics in CVDs. Particularly, HDACs, which are largely involved in promoting chromatin compaction and hence inhibitions of gene transcription, have been implicated in the pathogenic signalling underlying many aspects of CVDs. Recently, histone modiications have been demonstrated to play important roles in the angiogenesis process. Pharmacological inhibitions of HDACs have displayed promising therapeutic potentials in several pre-clinical models of CVDs where angiogenesis is of paramount importance. There are many evidences proving that pro-and anti-angiogenic therapies-and the impact of epigenetics in these processes-can help to artiicially reconstruct the vasculature in patients with cardiovascular diseases. Conversely, utilising knowledge of HDACs in angiogenesis might help to develop anti-angiogenic therapies in tackling diseases that are characterised with excessive pathological angiogenesis, including cancer and age-related macular degeneration. Understanding the molecular mechanisms underlying HDACs in modulating angiogenesis will undoubtedly beneit future therapeutics development. This chapter focuses on the emerging role of HDACs in angiogenesis and discuss their potentials and challenges in utilising HDAC inhibitors as therapeutics in several major cardiovascular diseases.

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“…Despite their remarkable potential for vascular regeneration in several diseases, clinical trials using EPCs have only been moderately successful (Fadini et al, 2012). However, the main obstacle to improving their vascular repair function could be a lack of understanding of the transcriptional network regulating their differentiation and proangiogenic activity (Fraineau et al, 2015).…”

Section: Epigenetic Modulation Of Epc Functions In Chfmentioning

confidence: 99%

“…Although a number of studies have shown that the process of histone acetylation/deacetylation plays a critical role in vascular development and ECs differentiation, little is known about EPCmediated vascular repair regulation by HATs and HDACs (Fraineau et al, 2015).…”

Section: Histone Modificationsmentioning

confidence: 99%