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BRD2 regulation of sigma-2 receptor upon cholesterol deprivation.
Life Science Alliance ( IF 4.4 ) Pub Date : 2020-11-24 , DOI: 10.26508/lsa.201900540
Hongtao Shen 1 , Jing Li 1 , Xiujie Xie 1 , Huan Yang 1 , Mengxue Zhang 1 , Bowen Wang 1 , K Craig Kent 1 , Jorge Plutzky 2 , Lian-Wang Guo 1, 3
Affiliation  

The sigma-2 receptor (S2R) has long been pharmacologically targeted for antipsychotic treatment and tumor imaging. Only recently was it known for its coding gene and for its role implicated in cholesterol homeostasis. Here, we have investigated the transcriptional control of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, and 4) upon cholesterol perturbation. Cholesterol deprivation was induced in ARPE19 cells using a blocker of lysosomal cholesterol export. This condition up-regulated S2R mRNA and protein, and also SREBP2 but not SREBP1, both transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD3 or BRD4 (though widely deemed a master regulator) averted S2R up-regulation that was induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, endogenous BRD2 co-immunoprecipitated with the transcription-active N-terminal half of SREBP2, and chromatin immunoprecipitation-qPCR signified co-occupancy of BRD2, H3K27ac (histone acetylation), and SREBP2Nterm at the S2R gene promoter. In summary, this study reveals a previously unrecognized BRD2/SREBP2 cooperative regulation of S2R transcription, thus shedding new light on signaling in response to cholesterol deprivation.

中文翻译:

BRD2 在胆固醇剥夺时对 sigma-2 受体的调节。

sigma-2 受体 (S2R) 长期以来一直是抗精神病治疗和肿瘤成像的药理学靶点。直到最近,人们才知道它的编码基因及其在胆固醇稳态中的作用。在这里,我们研究了 Bromo/ExtraTerminal 表观遗传阅读器家族(BET,包括 BRD2、3 和 4)在胆固醇扰动时对 S2R 的转录控制。使用溶酶体胆固醇输出阻断剂在 ARPE19 细胞中诱导胆固醇剥夺。这种情况会上调 S2R mRNA 和蛋白质,以及 SREBP2,但不会上调 SREBP1,这两种转录因子都是胆固醇/脂肪酸代谢的关键。沉默 BRD2 而不是 BRD3 或 BRD4(尽管被广泛认为是主要调节因子)可以避免由胆固醇剥夺引起的 S2R 上调。沉默 SREBP2 但不沉默 SREBP1 会减少 S2R 表达。此外,内源性 BRD2 与 SREBP2 转录活性 N 端的一半进行共免疫沉淀,染色质免疫沉淀-qPCR 表明 BRD2、H3K27ac(组蛋白乙酰化)和 SREBP2Nterm 在 S2R 基因启动子处共占据。总之,这项研究揭示了先前未被认识的 BRD2/SREBP2 对 S2R 转录的协同调节,从而为响应胆固醇剥夺的信号传导提供了新的线索。
更新日期:2020-11-27
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