TY - JOUR T1 - BRD2 regulation of sigma-2 receptor expression upon cytosolic cholesterol deprivation JF - bioRxiv DO - 10.1101/748236 SP - 748236 AU - Hongtao Shen AU - Jing Li AU - Xiujie Xie AU - Huan Yang AU - Mengxue Zhang AU - Bowen Wang AU - K. Craig Kent AU - Jorge Plutzky AU - Lian-Wang Guo Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/08/28/748236.abstract N2 - Traditionally a pharmacologic target for antipsychotic treatment, the sigma-2 receptor (S2R) was recently implicated in cholesterol homeostasis. Here we investigated the transcriptional regulation of S2R by the Bromo/ExtraTerminal epigenetic reader family (BETs, including BRD2, 3, 4) upon cholesterol perturbation.Cytosolic cholesterol deprivation was induced using an export blocker of lysosomal cholesterol in ARPE19 cells. This condition upregulated mRNA and protein levels of S2R, and of SREBP2 but not SREBP1, transcription factors key to cholesterol/fatty acid metabolism. Silencing BRD2 but not BRD4 (though widely deemed as a master regulator) or BRD3 prevented S2R upregulation induced by cholesterol deprivation. Silencing SREBP2 but not SREBP1 diminished S2R expression. Furthermore, BRD2 co-immunoprecipitated with the SREBP2 transcription-active N-terminal domain, and chromatin immunoprecipitation-qPCR showed a BRD2 occupancy at the S2R gene promoter.In summary, this study reveals a novel BRD2/SREBP2 cooperative regulation of S2R transcription in response to cytosolic cholesterol deprivation, thus shedding new light on epigenetic control of cholesterol biology. ER -