Narendra Varun, Bulajić Milica, Dekker Job, Mazzoni Esteban O, Reinberg Danny
Howard Hughes Medical Institute, New York, New York 10016, USA.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.
Genes Dev. 2016 Dec 15;30(24):2657-2662. doi: 10.1101/gad.288324.116.
The genome is organized into repeating topologically associated domains (TADs), each of which is spatially isolated from its neighbor by poorly understood boundary elements thought to be conserved across cell types. Here, we show that deletion of CTCF (CCCTC-binding factor)-binding sites at TAD and sub-TAD topological boundaries that form within the HoxA and HoxC clusters during differentiation not only disturbs local chromatin domain organization and regulatory interactions but also results in homeotic transformations typical of Hox gene misregulation. Moreover, our data suggest that CTCF-dependent boundary function can be modulated by competing forces, such as the self-assembly of polycomb domains within the nucleus. Therefore, CTCF boundaries are not merely static structural components of the genome but instead are locally dynamic regulatory structures that control gene expression during development.
基因组被组织成重复的拓扑相关结构域（TADs），每个TAD在空间上都与其相邻区域隔离，其边界元件尚不清楚，据认为在不同细胞类型中是保守的。在这里，我们表明，在分化过程中，HoxA和HoxC簇内形成的TAD和亚TAD拓扑边界处的CTCF（CCCTC结合因子）结合位点的缺失不仅会扰乱局部染色质结构域组织和调控相互作用，还会导致典型的Hox基因失调的同源异型转化。此外，我们的数据表明，依赖CTCF的边界功能可以被竞争力量调节，比如细胞核内多梳结构域的自组装。因此，CTCF边界不仅仅是基因组的静态结构成分，而是在发育过程中控制基因表达的局部动态调控结构。
