Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Division of Gene Regulation, Oncode Institute, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Cell. 2019 Sep 5;178(6):1437-1451.e14. doi: 10.1016/j.cell.2019.08.007.
CCCTC-binding factor (CTCF) and cohesin are key players in three-dimensional chromatin organization. The topologically associating domains (TADs) demarcated by CTCF are remarkably well conserved between species, although genome-wide CTCF binding has diverged substantially following transposon-mediated motif expansions. Therefore, the CTCF consensus motif poorly predicts TADs, and additional factors must modulate CTCF binding and subsequent TAD formation. Here, we demonstrate that the ChAHP complex (CHD4, ADNP, HP1) competes with CTCF for a common set of binding motifs. In Adnp knockout cells, novel insulated regions are formed at sites normally bound by ChAHP, whereas proximal canonical boundaries are weakened. These data reveal that CTCF-mediated loop formation is modulated by a distinct zinc-finger protein complex. Strikingly, ChAHP-bound loci are mainly situated within less diverged SINE B2 transposable elements. This implicates ChAHP in maintenance of evolutionarily conserved spatial chromatin organization by buffering novel CTCF binding sites that emerged through SINE expansions.
CCCTC 结合因子 (CTCF) 和黏连蛋白是三维染色质组织的关键参与者。由 CTCF 划定的拓扑关联域 (TAD) 在物种间具有显著的保守性,尽管在转座子介导的基序扩展之后,全基因组的 CTCF 结合已经发生了很大的变化。因此,CTCF 共有基序不能很好地预测 TAD,必须有其他因素来调节 CTCF 结合和随后的 TAD 形成。在这里,我们证明 ChAHP 复合物 (CHD4、ADNP、HP1) 与 CTCF 竞争一组常见的结合基序。在 Adnp 敲除细胞中,新型的绝缘区域形成于通常由 ChAHP 结合的位点,而近端的规范边界则减弱。这些数据表明,CTCF 介导的环形成受到一个独特的锌指蛋白复合物的调节。引人注目的是,ChAHP 结合的基因座主要位于分化程度较低的 SINE B2 转座元件内。这表明 ChAHP 通过缓冲因 SINE 扩展而出现的新的 CTCF 结合位点,在维持进化上保守的空间染色质组织方面发挥作用。