Cardiovascular disease is the leading cause of all deaths worldwide. Restenosis is the re-narrowing of a blood vessel after catheterization and can lead to down-stream heart problems even after surgical intervention. Researchers at University of Virginia used PLGA-PEG-PLGA (cat# AK012) from PolySciTech division of Akina, Inc. (www.polyscitech.com) to create a thermogelling delivery vehicle for EED226 to deliver it in place in the periadventitial space of the injured artery and observe its effects. This research holds promise to further understand and prevent in-stent restenosis. Read more: Zhang, Mengxue, Jing Li, Qingwei Wang, Go Urabe, Runze Tang, Yitao Huang, Jose Verdezoto Mosquera et al. "Gene-repressing epigenetic reader EED unexpectedly enhances cyclinD1 gene activation." Molecular Therapy-Nucleic Acids (2023). https://www.cell.com/molecular-therapy-family/nucleic-acids/pdf/S2162-2531(23)00044-6.pdf
“Epigenetically switched, proliferative vascular smooth muscle cells (SMCs) form neointima, engendering stenotic diseases. Histone-3 lysine-27 trimethylation (H3K27me3) and acetylation (H3K27ac) marks are associated with gene repression and activation, respectively. The polycomb protein embryonic ectoderm development (EED) reads H3K27me3 and also enhances its deposition, hence a canonical gene-repressor. However, herein we found an unexpected role for EED in activating the bona fide pro-proliferative gene Ccnd1 (cyclinD1). EED overexpression in SMCs increased Ccnd1 mRNA, seemingly contradicting its gene-repressing function. Yet consistently, EED co-immunoprecipitated with gene-activating H3K27ac reader BRD4, and they co-occupied at both mitogen-activated Ccnd1 and mitogen-repressed P57 (bona fide anti-proliferative gene), as indicated by chromatin immunoprecipitation-qPCR. These results were abolished by an inhibitor of either the EED/H3K27me3 or BRD4/H3K27ac reader function. In accordance, elevating BRD4 increased H3K27me3. In vivo, while EED was upregulated in rat and human neointimal lesions, selective EED inhibition abated angioplasty-induced neointima and reduced cyclinD1 in rat carotid arteries. Thus, results uncover a previously unknown role of EED in Ccnd1 activation, likely via its cooperativity with BRD4 that enhances each other’s reader function, i.e. activating pro-proliferative Ccnd1 while repressing anti-proliferative P57. As such, this study confers mechanistic implications for the epigenetic intervention of neointimal pathology.”
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