Epigenetics and vascular diseases

Stratton, Matthew S.; Farina, Floriana Maria; Elia, Leonardo

doi:10.1016/j.yjmcc.2019.06.010

Cited by 40 publications

(40 citation statements)

References 228 publications

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“…Histone methylation is defined as the transfer of methyl group from S-adenosyl-L-methionine to lysine or arginine residues of histone proteins by histone methyltransferases (HMTs) (86). Histone methyltransferases (HMTs) have higher specificity as compared to HATs (87) and include several families of enzymes (EZH, SETD, PRDM, PRMT, METTL, and MLL) (88). Recent evidence indicates that a fine balance between histone methylation and demethylation plays a pivotal role in the regulation of chromatin accessibility.…”

Section: Histone Modificationsmentioning

confidence: 99%

Epigenetic Control of Mitochondrial Function in the Vasculature

Mohammed

Ambrosini

Lüscher

et al. 2020

Front. Cardiovasc. Med.

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The molecular signatures of epigenetic regulation and chromatin architecture are emerging as pivotal regulators of mitochondrial function. Recent studies unveiled a complex intersection among environmental factors, epigenetic signals, and mitochondrial metabolism, ultimately leading to alterations of vascular phenotype and increased cardiovascular risk. Changing environmental conditions over the lifetime induce covalent and post-translational chemical modification of the chromatin template which sensitize the genome to establish new transcriptional programs and, hence, diverse functional states. On the other hand, metabolic alterations occurring in mitochondria affect the availability of substrates for chromatin-modifying enzymes, thus leading to maladaptive epigenetic signatures altering chromatin accessibility and gene transcription. Indeed, several components of the epigenetic machinery require intermediates of cellular metabolism (ATP, AcCoA, NADH, α-ketoglutarate) for enzymatic function. In the present review, we describe the emerging role of epigenetic modifications as fine tuners of gene transcription in mitochondrial dysfunction and vascular disease. Specifically, the following aspects are described in detail: (i) mitochondria and vascular function, (ii) mitochondrial ROS, (iii) epigenetic regulation of mitochondrial function; (iv) the role of mitochondrial metabolites as key effectors for chromatin-modifying enzymes; (v) epigenetic therapies. Understanding epigenetic routes may pave the way for new approaches to develop personalized therapies to prevent mitochondrial insufficiency and its complications.

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Section: Histone Modificationsmentioning

confidence: 99%

Epigenetic Control of Mitochondrial Function in the Vasculature

Mohammed

Ambrosini

Lüscher

et al. 2020

Front. Cardiovasc. Med.

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“…Epigenetic remodeling is increasingly recognized as crucial in cardiovascular pathologies such as IH 12 . The histone acetylation reader BRD4 and H3K27me3 writer EZH2 are powerful epigenetic regulators, as reported for proliferative diseases 11,14,26 and implicated for IH.…”

Section: Discussionmentioning

confidence: 99%

“…To this end, an imperative task is to understand BRD4-directed epigenetic mechanisms in the context of IH. While BRD4 is being intensively studied and clinically targeted in the cancer field 11 , SMC-specific BRD4 epigenomic/epigenetic regulations in IH pathogenesis remain poorly explored 12 .…”

Section: Introductionmentioning

confidence: 99%

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Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

Zhang

Wang

Urabe

et al. 2020

Preprint

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Atherosclerosis is commonly treated with angioplasty which, however, evokes neointimal hyperplasia (IH) and recurrent stenotic diseases. Epigenomic investigation was lacking on postangioplasty IH. The histone acetylation reader BRD4 and H3K27me3 writer EZH2 are potent epigenetic factors; their relationship is little understood. Through genome-wide survey in the rat angioplasty model, we studied BRD4 and EZH2 functional regulations involved in IH.We performed chromatin immunoprecipitation sequencing (ChIPseq) using rat carotid arteries. While H3K27me3 ChIPseq signal prevalently intensified in balloon-injured (vs uninjured) arteries, BRD4 and H3K27ac became more enriched at Ezh2. Indeed, BRD4-siRNA or CRISPR-deletion of BRD4-associated enhancer abated the smooth muscle cell (SMC) expression of EZH2, and SMC-specific BRD4 knockout in BRD4 fl/fl ; Myh11CreER T2 mice reduced both H3K27me3 and IH in wire-injured femoral arteries. In accordance, postangioplasty IH was exacerbated and mitigated, respectively, by lentiviral expression and pharmacological inhibition of EZH2/1; EZH2 (or EZH1) loss-and gain-of-function respectively attenuated and aggravated pro-IH SMC proliferative behaviors. Furthermore, while H3K27me3 ChIPseq signal magnified at P57 and ebbed at Ccnd1 and Uhrf1 after injury, silencing either EZH2 or EZH1 in SMCs up-regulated P57 and down-regulated Ccnd1 and Uhrf1.In summary, our results reveal an upsurge of EZH2/H3K27me3 after angioplasty, BRD4's control over EZH2 expression, and non-redundant EZH2/1 functions. As such, this study unravels angioplasty-induced loci-specific H3K27me3/ac redistribution in the epigenomic landscape rationalizing BRD4/EZH2-governed pro-IH regulations.

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“…Therefore, in the pursuit of new interventional paradigms, it is important to interpret the IH pathogenic mechanisms from an epigenetic perspective. However, epigenetic determinants of SMC state transitions only begin to be unveiled 2,3 .…”

Section: Introductionmentioning

confidence: 99%

Partnership between epigenetic reader BRD4 and transcription factor CEBPD

Wang

Zhang

Urabe³

et al. 2020

Preprint

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Vascular smooth muscle cell (SMC) state/phenotype transitions underlie neointimal hyperplasia (IH) predisposing to cardiovascular diseases. Bromodomain protein BRD4 is a histone acetylation reader and enhancer mark that co-activates transcription elongation. CCAAT enhancer binding protein delta (CEBPD) is a transcription factor typically studied in adipogenesis and immune cell differentiation. Here we investigated the association between BRD4 and CEBPD in SMC state transition.Chromatin immunoprecipitation sequencing (ChIPseq) showed enrichment of BRD4 and histone acetylation (H3K27ac) at Cebpd and enhancer in rat carotid arteries undergoing IH. In vitro, BRD4 silencing with siRNA reduced SMC expression of CEBPD. Bromodomain-1 but not bromodoamin-2 accounted for this BRD4 function. Endogenous BRD4 co-IP'ed with CEBPD; Cebpd promoter and enhancer DNA fragments co-IP'ed with CEBPD or endogenous BRD4 (ChIP-qPCR). These co-IPs were abolished by the BRD4 bromodomain blocker JQ1. TNFa upregulated both BRD4 and CEBPD. Silencing CEBPD averted TNFa-induced inflammatory SMC state transition (heightened IL-1b, IL6, and MCP-1 mRNA levels), so did JQ1. CEBPD overexpression increased PDGFRa preferentially over PDGFRb; so did TNFa, and JQ1 abolished TNFa's effect.Our data reveal a BRD4/CEBPD partnership that promotes CEBPD's own transcription and inflammatory SMC state transition, thus shedding new light on epigenetic reader and transcription factor cooperative actions in SMC pathobiology.

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Epigenetics and vascular diseases

Cited by 40 publications

References 228 publications

Epigenetic Control of Mitochondrial Function in the Vasculature

Epigenetic Control of Mitochondrial Function in the Vasculature

Angioplasty-induced epigenomic remodeling entails BRD4 and EZH2 hierarchical regulations

Partnership between epigenetic reader BRD4 and transcription factor CEBPD

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