Lutz M, Baniahmad A, Renkawitz R
Genetisches Institut, Justus-Liebig-Universität, D-35392 Giessen, Germany.
Biochem Soc Trans. 2000;28(4):386-9.
We have found that the thyroid hormone receptor (T3R) functionally synergizes with the CCCTC-binding factor (CTCF). CTCF is a highly conserved zinc-finger protein that has been connected with multiple functions in gene regulation including chromatin insulator activity, transcriptional enhancement and silencing as well as tumour suppression. A specific property of CTCF is that some of the binding sites are found in the vicinity of T3R-binding sites. Interestingly, both factors synergize in repression as well as in activation. T3R-mediated repression has been shown to involve co-repressors such as the silencing mediator for retinoic acid and thyroid hormone receptor (SMRT), N-CoR or Alien. These co-repressors in turn have been found to interact with Sin3A. Until now, the mechanisms by which CTCF synergizes with T3R in transcriptional repression has not been determined. Here we show that CTCF comprises autonomous silencing domains that mediate transcriptional repression when tethered to a promoter sequence. At least one of these domains, the zinc-finger region of CTCF, binds Sin3A without binding to SMRT or N-CoR and recruits histone deacetylation activity. For Sin3A we identified two different domains interacting independently with the CTCF zinc-finger cluster. The ability of regions of CTCF to retain deacetylase activity is correlated with the ability to bind to Sin3A and to repress transcription. Taking these results together, the synergy in repression mediated by T3R and CTCF might be achieved by the binding of multiple molecules of Sin3A to the T3R/CTCF-DNA complex, thus providing a large platform for the recruitment of histone deacetylases.
我们发现甲状腺激素受体（T3R）在功能上与CCCTC结合因子（CTCF）协同作用。CTCF是一种高度保守的锌指蛋白，在基因调控中具有多种功能，包括染色质绝缘子活性、转录增强和沉默以及肿瘤抑制。CTCF的一个特殊性质是，一些结合位点位于T3R结合位点附近。有趣的是，这两种因子在抑制和激活方面都能协同作用。T3R介导的抑制作用已被证明涉及共抑制因子，如视黄酸和甲状腺激素受体沉默介质（SMRT）、N-CoR或Alien。这些共抑制因子反过来又被发现与Sin3A相互作用。到目前为止，CTCF与T3R在转录抑制中协同作用的机制尚未确定。在这里，我们表明CTCF包含自主沉默结构域，当与启动子序列相连时，这些结构域介导转录抑制。这些结构域中至少有一个，即CTCF的锌指区域，与Sin3A结合而不与SMRT或N-CoR结合，并募集组蛋白去乙酰化活性。对于Sin3A，我们鉴定出两个不同的结构域，它们独立地与CTCF锌指簇相互作用。CTCF区域保留去乙酰化酶活性的能力与结合Sin3A和抑制转录的能力相关。综合这些结果，T3R和CTCF介导的抑制协同作用可能是通过多个Sin3A分子与T3R/CTCF-DNA复合物结合来实现的，从而为募集组蛋白去乙酰化酶提供了一个大平台。
