BRD2 regulation of sigma-2 receptor upon cholesterol deprivation

• DOI: 10.26508/lsa.201900540
• Publication Date: 2020-11-24T19:52:26Z
• Authors: Hongtao Shen; Jing Li; Xiujie Xie; Huan Yang; Mengxue Zhang; Bowen Wang; K Craig Kent; Jorge Plutzky; Lian-Wang Guo
• Keywords: Chromatin immunoprecipitation; Orphan receptor

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