Long noncoding RNA Chaer mediated Polycomb Repressor Complex 2 (PRC2) activity to promote atherosclerosis through mTOR signaling

摘要

OBJECTIVE: Recent studies highlighted long noncoding RNAs (lncRNAs) have been implicated in many biological processes and diseases. However, atherosclerosis is a major risk factor for cardiovascular disease, but the detailed mechanism of atherosclerosis progression remained unclear. In this study, we mainly focused on the role of lncRNA Chaer in atherosclerosis. PATIENTS AND METHODS: RT-PCR was used to detect the expression of lncRNA Chaer in atherosclerosis patients and animal model. Moreover, the expression of Chaer in vascular smooth muscle cell dysfunction model was also measured. Proliferation ability was tested by CCK-8 and cyclin D1 assay, through loss- and gain-of-function approaches. Western-blot was used to measure the expression of H3 lysine 27 methylation, when Chaer was in different levels. RIP and ChIP assay discovered an interaction between Chaer and PRC2 through mTOR signaling. RESULTS: Here we identified a heart-enriched long non-coding RNA, named Cardiac Hypertrophy Associated Epigenetic Regulator (Chaer). We found that the Chaer was highly expressed in serum samples from 28 patients with atherosclerosis, compared with 28 healthy volunteers. Chaer was dramatically upregulated in atherosclerotic plaques of ApoE-/- mice. We also found that the expression of Chaer was upregulated in vascular smooth muscle cell injury model. Through loss- and gain-of-function approaches, we showed that Chaer promotes cell proliferation and induces apoptosis in vitro. Mechanistically, Chaer interacts with Polycomb Repressor Complex 2 (PRC2) through inhibiting histone H3 lysine 27 methylation. Further, this interaction is induced upon mTOR signaling pathway. CONCLUSIONS: According to the results, we found that lncRNA Chaer was closely related to the progression of atherosclerosis, which could be a previously uncharacterized lncRNA-dependent epigenetic checkpoint.