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Angioplasty induces epigenomic remodeling in injured arteries
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  • Mengxue Zhang,
  • Bowen Wang,
  • Go Urabe,
  • Gulcin Ozer,
  • Renzhi Han,
  • Craig Kent,
  • Lian-Wang Guo
Mengxue Zhang
University of Virginia
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Bowen Wang
University of Virginia
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Go Urabe
University of Virginia
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Gulcin Ozer
University of Virginia
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Renzhi Han
University of Virginia
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Craig Kent
University of Virginia
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Lian-Wang Guo
University of Virginia

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Abstract

Background: Neointimal hyperplasia (IH) is the primary etiology of stenotic vascular diseases. It is perpetuated principally by smooth muscle cell (SMC) proliferation -an epigenetic event. Epigenome-scale studies concerning IH have been confined to in vitro models, and the epigenetic mechanisms governing SMC/neointima proliferation are not well understood. Experimental Approach: Using an IH-inducing angioplasty model in rat carotid arteries, we performed chromatin immunoprecipitation coupled with high-throughput sequencing (ChIPseq) to determine epigenomic remodeling. Key Results: Angioplasty induced a genome-wide surge of histone-3/lysine-27 trimethylation (H3K27me3), a gene repression mark. This was unexpected, as gene activation rather than repression is traditionally regarded as dominating neointima proliferation. ChIPseq further revealed the co-localization of gene activation mark H3K27ac(acetylation) with its reader BRD4 at the gene of H3K27me3 writer -enhancer of zeste homolog-2 (EZH2). Accordingly, EZH2 expression was abated by either BRD4-silencing or deletion of BRD4/H3K27ac-associated enhancer in SMCs. In vivo, while SMC-specific BRD4 knockout in BRD4fl/fl; Myh11CreERT2 mice reduced H3K27me3 and IH in wire-injured arteries, EZH2 loss- and gain-of-function respectively mitigated and exacerbated IH in rat arteries. Furthermore, angioplasty induced a shift of H3K27me3 ChIPseq-peaks from pro-proliferative genes (e.g. Uhrf1, Ccnd1) to anti-proliferative genes such as Cdkn1c, in favor of de-repression of the former and repression of the latter. Conclusion and Implications: This study unravels angioplasty-induced loci-specific H3K27me3 redistribution in the epigenomic landscape that entails BRD4->EZH2 hierarchical regulations. The new knowledge may lend implications for treating IH, given that EZH2 and BRD4 are both pharmacological targets in human trials.