The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor
The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor
复制标题
DOI：
10.1128/mcb.23.15.5122-5131.2003
复制
发表时间：
2003-08-01
影响因子：
5.3
通讯作者：
Lazar, MA
中科院分区：
文献类型：
--
作者：
Ishizuka, T;Lazar, MA
核受体辅抑制因子（N-CoR）和类视黄酮和甲状腺受体的沉默介质（SMRT）都与甲状腺激素受体（TR）介导的抑制有关。在这里，我们发现内源性N-CoR、TBL1和组蛋白去乙酰化酶3 (HDAC3)，而不是HDAC1、-2或-4，被募集到一个稳定整合的报告基因中，该报告基因受到未配体TR和孤儿受体RevErb的抑制。未配体的TR也将该复合体招募到瞬时转染的报告基因中，转录抑制与局部组蛋白去乙酰化有关，而这种去乙酰化被甲状腺激素的存在所逆转。在人293T细胞中，使用小干扰rna敲低N-CoR可显著降低TR配体结合域的抑制，而敲低SMRT则几乎没有影响。在这个系统中，混响抑制似乎涉及两种共抑制因子。敲低HDAC3可显著降低TR和RevErb的抑制作用，而敲低HDAC1或2则具有较为温和的部分非特异性作用。因此，HDAC3对多种核受体的抑制至关重要，N-CoR HDAC3复合物在人293T细胞中tr介导的基因抑制中起着独特而必要的作用。
Nuclear receptor corepressors (N-CoR) and silencing mediator for retinoid and thyroid receptors (SMRT) have both been implicated in thyroid hormone receptor (TR)-mediated repression. Here we show that endogenous N-CoR, TBL1, and histone deacetylase 3 (HDAC3), but not HDAC1, -2, or -4, are recruited to a stably integrated reporter gene repressed by unliganded TR as well as the orphan receptor RevErb. Unliganded TR also recruits this complex to a transiently transfected reporter, and transcriptional repression is associated with local histone deacetylation that is reversed by the presence of thyroid hormone. Knockdown of N-CoR using small interfering RNAs markedly reduces repression by the TR ligand binding domain in human 293T cells, whereas knockdown of SMRT has little effect. RevErb repression appears to involve both corepressors in this system. Knockdown of HDAC3 markedly reduces repression by both TR and RevErb, while knockdown of HDAC1 or 2 has more modest, partly nonspecific effects. Thus, HDAC3 is critical for repression by multiple nuclear receptors and the N-CoR HDAC3 complex plays a unique and necessary role in TR-mediated gene repression in human 293T cells.