Cholesterol is required for transcriptional repression by BASP1.
Cholesterol is required for transcriptional repression by BASP1.
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DOI：
10.1073/pnas.2101671118
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发表时间：
2021-07-20
影响因子：
11.1
通讯作者：
Roberts SGE
中科院分区：
文献类型：
--
作者：
Loats AE;Carrera S;Fleming AF;Roberts ARE;Sherrard A;Toska E;Moorhouse AJ;Medler KF;Roberts SGE
胆固醇存在于细胞核内，与染色质结合，但迄今为止，胆固醇在核过程中的直接作用尚未确定。我们证明转录抑制因子脑酸可溶蛋白 1 (BASP1) 通过共有的胆固醇相互作用基序直接与细胞核内的胆固醇相互作用。 BASP1 将胆固醇招募到靶基因的启动子区域，在该区域介导染色质重塑和转录抑制。我们的工作表明胆固醇在转录调节中发挥直接作用。脂质存在于细胞核内，在那里它们与参与基因调控的因子结合。胆固醇在体内与染色质结合并在体外刺激核小体堆积，但其对特定转录反应的影响尚不清楚。在这里，我们证明脂化肾母细胞瘤 1 (WT1) 转录辅阻遏物脑酸可溶性蛋白 1 (BASP1) 通过保守的胆固醇相互作用基序与细胞核中的胆固醇相互作用。我们证明 BASP1 直接将胆固醇招募到 WT1 靶基因的启动子区域。 BASP1 的突变消除了它与胆固醇的相互作用，或者用阻断胆固醇生物合成的药物治疗细胞会抑制 BASP1 的转录阻遏功能。我们发现 BASP1-胆固醇相互作用是 BASP1 依赖性染色质重塑和控制细胞分化的转录程序方向所必需的。我们的研究揭示了一种基因特异性靶向胆固醇的机制，它需要介导转录抑制。
Cholesterol is present within the cell nucleus, where it associates with chromatin, but to date, a direct role for cholesterol in nuclear processes has not been identified. We demonstrate that the transcriptional repressor brain acid soluble protein 1 (BASP1) directly interacts with cholesterol within the cell nucleus through a consensus cholesterol interaction motif. BASP1 recruits cholesterol to the promoter region of target genes, where it is required to mediate chromatin remodeling and transcriptional repression. Our work demonstrates that cholesterol plays a direct role in transcriptional regulation. Lipids are present within the cell nucleus, where they engage with factors involved in gene regulation. Cholesterol associates with chromatin in vivo and stimulates nucleosome packing in vitro, but its effects on specific transcriptional responses are not clear. Here, we show that the lipidated Wilms tumor 1 (WT1) transcriptional corepressor, brain acid soluble protein 1 (BASP1), interacts with cholesterol in the cell nucleus through a conserved cholesterol interaction motif. We demonstrate that BASP1 directly recruits cholesterol to the promoter region of WT1 target genes. Mutation of BASP1 to ablate its interaction with cholesterol or the treatment of cells with drugs that block cholesterol biosynthesis inhibits the transcriptional repressor function of BASP1. We find that the BASP1–cholesterol interaction is required for BASP1-dependent chromatin remodeling and the direction of transcription programs that control cell differentiation. Our study uncovers a mechanism for gene-specific targeting of cholesterol where it is required to mediate transcriptional repression.
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影响因子：
9
作者：
Marsh LA;Carrera S;Shandilya J;Heesom KJ;Davidson AD;Medler KF;Roberts SG
通讯作者：
Roberts SG
影响因子：
5.4
作者：
Epand, RF;Sayer, BG;Epand, RM
通讯作者：
Epand, RM
DOI：
10.1083/jcb.201507122
发表时间：
2016-01-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ohsaki Y;Kawai T;Yoshikawa Y;Cheng J;Jokitalo E;Fujimoto T
通讯作者：
Fujimoto T
影响因子：
4.1
作者：
Epand, RM;Vuong, P;Epand, RF
通讯作者：
Epand, RF
影响因子：
4.4
作者：
Garcia-Gil, Mercedes;Albi, Elisabetta
通讯作者：
Albi, Elisabetta