Abstract
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.
Highlights
After decades of studies, cholesterol biology remains inadequately understood, in particular, the regulations involving lysosomes, which distribute cholesterol to other organelles [1]
We found that BETs inhibition repressed the transcription of both SREBP1 and SREBP2, the master transcription factors (TFs) governing fatty acid and cholesterol homeostasis, and silencing SREBP2 but not SREBP1 inhibited sigma-2 receptor (S2R) expression
We used U18666A as a tool to generate an experimental condition for cholesterol deprivation, as it is an established NPC1 inhibitor that keeps cholesterol trapped inside the lysosome thereby producing an intracellular environment with cholesterol reduced in the ER (17 Preprint, 18)
Summary
Cholesterol biology remains inadequately understood, in particular, the regulations involving lysosomes, which distribute cholesterol to other organelles [1]. Though an ER resident protein, TMEM97 can translocate to the lysosomal membrane where it appears to attenuate the activity of NPC1 (Niemann–Pick disease, type C) [3], the transporter that “pumps” cholesterol out of the lysosome. There are a very small number of articles published on TMEM97 ( known as MAC30) [5]; studies on S2R are largely limited to pharmacology such as anti-psychotic treatments [6]. Silencing S2R appeared to alleviate Niemann–Pick disease condition in a mouse model, which features mutated NPC1 and consequential cholesterol accumulation in lysosomes [2]. It is, important to understand how S2R expression is controlled, whereas little is known at present
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