BRD2 regulation of sigma-2 receptor upon cholesterol deprivation.
BRD2 regulation of sigma-2 receptor upon cholesterol deprivation.
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DOI：
10.26508/lsa.201900540
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发表时间：
2021-01
影响因子：
4.4
通讯作者：
Guo LW
中科院分区：
文献类型：
--
作者：
Shen H;Li J;Xie X;Yang H;Zhang M;Wang B;Kent KC;Plutzky J;Guo LW
胆固醇剥夺后，表观遗传书签阅读器BRD 2和主转录因子SREBP 2在书签染色质（H3 K27 ac）处形成复合物，从而激活sigma-2受体的转录-最近公布的胆固醇稳态参与者。sigma-2受体（S2 R）长期以来一直是抗精神病药物治疗和肿瘤成像的靶点。直到最近才知道它的编码基因和它在胆固醇稳态中的作用。在这里，我们已经调查了转录控制S2 R的Bromo/ExtraTerminal表观遗传阅读器家族（BET，包括BRD 2，3和4）胆固醇扰动。使用溶酶体胆固醇输出的阻断剂在ARPE 19细胞中诱导胆固醇剥夺。这种情况下上调S2 R mRNA和蛋白，以及SREBP 2，但不是SREBP 1，这两种转录因子都是胆固醇/脂肪酸代谢的关键。沉默BRD 2而不是BRD 3或BRD 4（尽管广泛认为是主调节因子）可以避免胆固醇剥夺诱导的S2 R上调。沉默SREBP 2而不是SREBP 1减少了S2 R表达。此外，内源性BRD 2与SREBP 2的转录活性N-末端的一半共免疫沉淀，染色质免疫沉淀-qPCR表示BRD 2、H3 K27 ac（组蛋白乙酰化）和SREBP 2Nterm在S2 R基因启动子处的共占据。总之，这项研究揭示了以前未被识别的BRD 2/SREBP 2合作调节S2 R转录，从而揭示了响应胆固醇剥夺的信号转导。
Upon cholesterol deprivation, epigenetic bookmark reader BRD2 and master transcription factor SREBP2 form a complex at bookmarked chromatin (H3K27ac), thereby activating the transcription of the sigma-2 receptor—a recently unveiled player in cholesterol homeostasis. 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.
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影响因子：
16
作者：
Sakamaki JI;Wilkinson S;Hahn M;Tasdemir N;O'Prey J;Clark W;Hedley A;Nixon C;Long JS;New M;Van Acker T;Tooze SA;Lowe SW;Dikic I;Ryan KM
通讯作者：
Ryan KM
影响因子：
16.6
作者：
Lee JE;Park YK;Park S;Jang Y;Waring N;Dey A;Ozato K;Lai B;Peng W;Ge K
通讯作者：
Ge K
TM6SF2和MAC30，固醇代谢和常见代谢疾病的新酶同源物。
影响因子：
3.7
作者：
Sanchez-Pulido L;Ponting CP
通讯作者：
Ponting CP
DOI：
10.1073/pnas.1711155115
发表时间：
2018-02-27
影响因子：
11.1
作者：
Brown JD;Feldman ZB;Doherty SP;Reyes JM;Rahl PB;Lin CY;Sheng Q;Duan Q;Federation AJ;Kung AL;Haldar SM;Young RA;Plutzky J;Bradner JE
通讯作者：
Bradner JE
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS