Abstract
Neointimal hyperplasia/proliferation (IH) is the primary etiology of vascular stenosis. Epigenomic studies concerning IH have been largely confined to in vitro models, and IH-underlying epigenetic mechanisms remain poorly understood. This study integrates information from in vivo epigenomic mapping, conditional knockout, gene transfer and pharmacology in rodent models of IH. The data from injured (IH-prone) rat arteries revealed a surge of genome-wide occupancy by histone-3 lysine-27 trimethylation (H3K27me3), a gene-repression mark. This was unexpected in the traditional view of prevailing post-injury gene activation rather than repression. Further analysis illustrated a shift of H3K27me3 enrichment to anti-proliferative genes, from pro-proliferative genes where gene-activation mark H3K27ac(acetylation) accumulated instead. H3K27ac and its reader BRD4 (bromodomain protein) co-enriched at Ezh2; conditional BRD4 knockout in injured mouse arteries reduced H3K27me3 and its writer EZH2, which positively regulated another pro-IH chromatin modulator UHRF1. Thus, results uncover injury-induced loci-specific H3K27me3 redistribution in the epigenomic landscape entailing BRD4→EZH2→UHRF1 hierarchical regulations. Given that these players are pharmaceutical targets, further research may help improve treatments of IH.
Highlights
Neointimal hyperplasia (IH) in the inner vascular wall obstructs blood flow engendering cardiovascular diseases
We collected the arteries at post-angioplasty day 7, the peak time of a myriad of pro-Intimal hyperplasia (IH) molecular and cellular events such as proproliferative gene activation (Marx et al, 2011; Saito et al, 2011; Wang et al, 2015; Shi et al, 2019)
Our results indicated that EZH2 and EZH1 were non-redundant in promoting the pro-IH smooth muscle cells (SMCs) behaviors
Summary
Neointimal hyperplasia (IH) in the inner vascular wall obstructs blood flow engendering cardiovascular diseases. Without DNA sequence changes − this SMC state transition is epigenetic in its nature (Gomez et al, 2015; Wang et al, 2015; Das et al, 2017). A number of epigenetic factors, mainly DNA and histone modification enzymes, are known players in SMC proliferation and IH (Gomez et al, 2015), and mostly studied with a focus on pro-proliferative gene activation (Marx et al, 2011; Byrne et al, 2015). BRD4, a bromo and extraterminal (BET) family histone mark reader and gene coactivator, was suggested to be a determinant of SMC proliferation and IH (Wang et al, 2015; Dutzmann et al, 2021) whereas this remained to be verified through tissue-specific BRD4 KO. Whereas gene activation has been the mainstay of mechanistic studies on SMC/ neointima proliferation, gene repression is often overlooked
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