Divergent Requirements for EZH1 in Heart Development Versus Regeneration

Ai, Shanshan; Yu, Xianhong; Li, Yumei; Peng, Yong; Li, Chen; Yue, Yanzhu; Tao, Ge; Li, Chuanyun; Pu, William T.; He, Aibin

doi:10.1161/circresaha.117.311212

Cited by 68 publications

(64 citation statements)

References 19 publications

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“…This complex is closely associated with cell differentiation, development, and various cancers (Moritz & Trievel, ). The methyltransferase core, enhancer of zeste homologue 2/1 (EZH2/1), is the core component of PRC2, found to be involved in heart development, pulmonary arterial hypertension, and aortic dissection (Ai et al, ; Aljubran et al, ; Li et al, ). However, whether PRC2‐mediated methylation of H3K27 is involved in restenosis post‐angioplasty is unknown.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of polycomb repressor complex 2 ameliorates neointimal hyperplasia by suppressing trimethylation of H3K27 in vascular smooth muscle cells

Liang

Cai

et al. 2019

British J Pharmacology

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Background and Purpose The increased proliferation and migration of vascular smooth muscle cells (VSMCs) after arterial injury contributes greatly to the pathogenesis of neointimal hyperplasia. As a major component of epigenetics, histone methylation plays an important role in several cardiovascular diseases. However, its role in restenosis is still unclear. Experimental Approach Human aortic VSMCs were challenged with PDGF‐BB, and total histones were extracted and analysed by HPLC/MS. For the in vivo study, rats were subjected to wire‐guided common carotid injury. Key Results PDGF‐BB markedly increased the H3K27me3 level, as demonstrated by use of HPLC/MS and confirmed by western blot analysis. Enhancer of zeste homologue 2 (EZH2), the histone H3K27 methyltransferase component of polycomb repressive complex 2, was also up‐regulated by PDGF‐BB in VSMCs, and in the neointimal hyperplasia induced by wire injury of the rat carotid artery. Furthermore, inhibiting H3K27me3 by treatment with 3‐μM UNC1999, an EZH2/1 inhibitor, significantly suppressed PDGF‐BB‐induced VSMC proliferation compared with the PDGF‐BB‐treated group. Consistently, neointimal formation was significantly attenuated by oral or perivascular administration of UNC1999 compared with the sham group. Mechanistically, the increase in H3K27me3 inhibited the transcription of the cyclin‐dependent kinase inhibitor p16INK4A and thus promoted VSMC proliferation. Conclusions and Implications Vascular injury elevated the expression of EZH2 and the downstream target H3K27me3, which suppressed p16INK4A expression in VSMCs and promoted VSMC proliferation and neointimal hyperplasia. EZH2 inhibition might be a potential therapeutic target for restenosis.

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Section: Introductionmentioning

confidence: 99%

Inhibition of polycomb repressor complex 2 ameliorates neointimal hyperplasia by suppressing trimethylation of H3K27 in vascular smooth muscle cells

Liang

Cai

et al. 2019

British J Pharmacology

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“…While tracing the factor(s) underlying enhanced H3K27me3, which is known to be deposited primarily by EZH2 13 , we noticed greater BRD4 and H3K27ac enrichment at Ezh2 in injured vs uninjured arteries. This data led us to investigate whether BRD4 regulated EZH2 expression given that both BRD4 and H3K27ac are enhancer marks typically associated with transcriptional activation 26 .…”

Section: Discussionmentioning

confidence: 79%

“…In addition to EZH2, the EZH1 isoform also methylates H3K27 13 . However, EZH1 is much less studied.…”

Section: Ezh2 and Ezh1 Each Promotes Ih In Balloon-injured Rat Carotimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In contrast to BRD4's function of co-activating transcription 8 , enhancer of zeste homologs (EZH2 and EZH1 isoforms) catalyze methylation at H3K27 leading to transcriptional repression 13,14 . EZH2 recently emerged as a driver of cell state transitions such as cancer cell proliferation and migration, yet reports on EZH1 are limited and discrepant regarding its redundancy with EZH2 13,15 . Pharmacological evidence from our 16 and other groups 17,18 supports an IH-mitigating effect of pan-EZH1/2 inhibition, underscoring the importance of dissecting their functional roles and the mechanisms governing their expression levels.…”

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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