Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation.
Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation.
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DOI：
10.1093/nar/gkq227
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发表时间：
2010-08
影响因子：
14.9
通讯作者：
Choi HS
中科院分区：
文献类型：
--
作者：
Chanda D;Xie YB;Choi HS
孤儿核受体小异二聚体伴侣(SHP；NR0B2)是多种核受体(NRs)的转录辅阻遏子。在这里，我们报告了SHP以NR特异性的方式招募SIRT1，一种III类组蛋白去乙酰基酶，以抑制转录活性。SHP在体内与SIRT1相互作用并共同定位，抑制SIRT1的活性可以恢复SHP的内在抑制活性，但不能恢复DAX1的抑制活性。此外，我们观察到SIRT1不能去乙酰化SHP或LRH1。然而，抑制SIRT1或SHP均可显著减弱SHP对LRH1反式反应的抑制作用。SHP和SIRT1均能显著抑制LRH1介导的细胞色素P7A1和SHP基因转录的激活，而抑制SIRT1活性或显性负性SIRT1或SHP的敲除可使这种抑制作用显着释放。芯片分析显示，SHP在LRH1靶基因启动子上招募SIRT1，SIRT1去乙酰化模板依赖的组蛋白H3和H4来抑制LRH1靶基因的转录。最后，我们证明了SIRT1活性的抑制显著逆转了SHP通过LRH1过表达对胆汁酸合成的抑制，从而暗示了SHP通过重新募集SIRT1组蛋白去乙酰基酶蛋白来抑制LRH1依赖的胆汁酸稳态的新机制。
Orphan nuclear receptor Small Heterodimer Partner (SHP; NR0B2) is a transcriptional corepressor of a wide variety of nuclear receptors (NRs). Here, we report that SHP recruits SIRT1, a class III histone deacetylase, in an NR-specific manner to inhibit transcriptional activity. SHP interacts and co-localizes specifically with SIRT1 in vivo and inhibition of SIRT1 activity leads to a recovery from the intrinsic repressive activity of SHP but not of DAX1. Furthermore, we observed that SIRT1 does not deacetylate SHP or LRH1. However, inhibition of either SIRT1 or SHP significantly diminished the repressive effect of SHP on LRH1 transactivity. LRH1-mediated activation of CYP7A1 and SHP gene transcription was significantly repressed by both SHP and SIRT1 whereas inhibition of SIRT1 activity by inhibitors or dominant negative SIRT1 or knockdown of SHP led to a significant release of this inhibitory effect. ChIP assays revealed that SHP recruits SIRT1 on LRH1 target gene promoters and SIRT1 deacetylated template-dependent histone H3 and H4 to inhibit transcription of LRH1 target genes. Finally, we demonstrated that inhibition of SIRT1 activity significantly reversed SHP-mediated inhibition of bile-acid synthesis by LRH1 overexpression, thereby suggesting a novel mechanism of SHP-mediated inhibition of LRH1-dependent bile-acid homeostasis via recruitment of SIRT1 histone deacetylase protein.
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影响因子：
4.8
作者：
Nedumaran, Balachandar;Hong, Sungpyo;Choi, Hueng-Sik
通讯作者：
Choi, Hueng-Sik
影响因子：
4
作者：
Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
14.9
作者：
Boulias, K;Talianidis, I
通讯作者：
Talianidis, I
影响因子：
--
作者：
Park, YY;Kim, HJ;Choi, HS
通讯作者：
Choi, HS
影响因子：
2.9
作者：
Gobinet, J;Carascossa, S;Jalaguier, S
通讯作者：
Jalaguier, S