PT  - JOURNAL ARTICLE
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
TI  - BRD2 regulation of sigma-2 receptor upon cholesterol deprivation
AID  - 10.26508/lsa.201900540
DP  - 2021 Jan 01
TA  - Life Science Alliance
PG  - e201900540
VI  - 4
IP  - 1
4099  - https://www.life-science-alliance.org/content/4/1/e201900540.short
4100  - https://www.life-science-alliance.org/content/4/1/e201900540.full
SO  - Life Sci. Alliance2021 Jan 01; 4
AB  - 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.