Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
Nat Commun. 2020 Aug 17;11(1):4133. doi: 10.1038/s41467-020-17955-2.
Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. In this report, we demonstrate that the CCCTC-binding factor (CTCF), a crucial chromatin organizer, is essential for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of CTCF or its deletion blocks Schwann cell differentiation at the pro-myelinating stage, whereas overexpression of CTCF promotes the myelination program. We find that CTCF establishes chromatin interaction loops between enhancer and promoter regulatory elements and promotes expression of a key pro-myelinogenic factor EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2 (PRC2), to repress the transcriptional program associated with negative regulation of Schwann cell maturation. Together, our findings reveal a dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block Schwann cell differentiation inhibitors to control peripheral myelination and repair.
染色质组织对于细胞生长、分化和疾病发展至关重要，然而，其在外周髓鞘形成和髓鞘修复中的功能仍然难以捉摸。在本报告中，我们证明了 CCCTC 结合因子（CTCF），一种关键的染色质组织蛋白，对于施万细胞髓鞘形成和神经损伤后的髓鞘再生是必不可少的。CTCF 的抑制或缺失会阻止施万细胞在促髓鞘形成阶段分化，而 CTCF 的过表达则促进髓鞘形成程序。我们发现 CTCF 在增强子和启动子调控元件之间建立染色质相互作用环，并促进关键的促髓鞘形成因子 EGR2 的表达。此外，CTCF 与多梳抑制复合物 2（PRC2）的组成部分 SUZ12 相互作用，以抑制与施万细胞成熟负调控相关的转录程序。总之，我们的发现揭示了 CTCF 依赖性染色质组织在促进髓鞘形成程序和招募染色质抑制复合物以阻止施万细胞分化抑制剂以控制外周髓鞘形成和修复方面的双重作用。
