EZH2 as an Epigenetic Regulator of Cardiovascular Development and Diseases

Abstract

Enhancer of zeste homolog 2(EZH2) is an enzymatic subunit of polycomb repressive complex 2 (PRC2) and is responsible for catalyzing mono-, di-, and trimethylation of histone H3 at lysine-27(H3K27me1/2/3). Many noncoding RNAs or signaling pathways are involved in EZH2 functional alterations. This new epigenetic regulation of target genes is able to silence downstream gene expression and modify physiological and pathological processes in heart development, cardiomyocyte regeneration, and cardiovascular diseases, such as hypertrophy, ischemic heart diseases, atherosclerosis, and cardiac fibrosis. Targeting the function of EZH2 could be a potential therapeutic approach for cardiovascular diseases.

Astronauts Plasma-Derived Exosomes Induced Aberrant EZH2-Mediated H3K27me3 Epigenetic Regulation of the Vitamin D Receptor

“…EZH2 overexpression and gain-of-function mutations are associated with aberrantly high H3K27 trimethylation levels and repression of target genes related to cell cycle progression, proliferation, apoptosis, autophagy, senescence, and inflammation ( 29 – 31 ). As a result, further studies have associated dysregulation of EZH2 with various diseases, including CVD (cardiac hypertrophy, fibrosis, atherosclerosis, ischemic heart disease, myocardial regeneration, cardiomyopathy, pulmonary arterial hypertension, atrial fibrillation) ( 26 , 32 – 37 ), various solid cancers (lung, breast, endometrial, ovarian, nasopharyngeal, thyroid, liver, prostate, and glioblastoma) ( 8 , 17 , 38 – 40 ), as well as hematopoietic cancers (Non-Hodgkin's, large B-cell, and follicular lymphoma) ( 41 , 42 ). Preclinical studies investigating inhibition of EZH2, primarily with inhibitors GSK126 and EPZ6437 (Tazemetostat), have been promising in both CVD and cancer ( 30 , 39 , 43 – 47 ) and have led to early phase clinical trials in the context of various lymphomas and advanced solid tumors (NCT01897571), mesothelioma (NCT02860286), sarcoma (NCT02601950).…”

Roles of Epigenetics in Cardiac Fibroblast Activation and Fibrosis

“…Among them, enhancer of zeste homologue 2 (EZH2), a member of the EZH family, is most widely studied. EZH2 acts as the main catalytic subunit of the Polycomb repressive complex 2 (PRC2), which specifically catalyzes the methylation of histone H3 at lysine-27 (H3K27me1/me2/me3) through the SET structural domain [ 117 ]. EZH2 acts as an important epigenetic regulator during cardiac development and disease progression [ 117 , 118 , 119 ].…”

Long Non-Coding RNA Regulation of Epigenetics in Vascular Cells

“…PRC2 comprises four major subunits including EZH2 (enhancer of zeste homolog 2) which possesses the catalytic histone methyltransferase SET domain; EED (embryonic ectoderm development) which binds the H3K27me3 mark and is responsible for its propagation; SUZ12 (suppressor of zeste 12 homolog); and RbAp46/48 (retinoblastoma protein associated protein 46/48) (Figure 3) [57]. The mechanisms behind PRC2 engagement with native chromatin, as well as its recruitment in a context-dependent manner, remain to be fully understood [58]. EZH2mediated epigenomic landscapes guide cardiovascular and endothelial differentiation and maturation, maintain tissue-specific genetic blueprints established during development, and are implicated in cardiovascular disease [55,57,58].…”

“…The mechanisms behind PRC2 engagement with native chromatin, as well as its recruitment in a context-dependent manner, remain to be fully understood [58]. EZH2mediated epigenomic landscapes guide cardiovascular and endothelial differentiation and maturation, maintain tissue-specific genetic blueprints established during development, and are implicated in cardiovascular disease [55,57,58]. Moreover, PRC2 histone methyltransferase activity appears to be a key regulator of angiogenesis.…”