CTCF-dependent chromatin architecture and SUZ12/PRC2 complex recruitment are required for peripheral myelination and repair

Chromatin organization is critical for cell growth, differentiation, and disease development, however, its functions in peripheral myelination and myelin repair remain elusive. Here we observed a global diminution of chromatin accessibility during Schwann cell differentiation and demonstrated that the chromatin organizer CCCTC-binding factor (CTCF) is critical for Schwann cell myelination and myelin regeneration after nerve injury. Inhibition of Ctcf or its deletion blocked Schwann cell differentiation at the pre-myelinating stage, whereas overexpression of CTCF promoted the myelination program. CTCF establishes the chromatin interaction loop between promoters and regulatory elements to promote expression of key pro-myelinogenic factors such as EGR2. In addition, CTCF interacts with SUZ12, a component of polycomb-repressive-complex 2, to repress expression of immature Schwann cell-associated regulators including HES1, RSPO2, and CALCA. Together, our findings reveal the dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block differentiation inhibitors to control peripheral myelination and myelin repair.染色质组织对于细胞生长、分化及疾病发生至关重要，然而其在外周髓鞘形成与髓鞘修复中的功能仍有待阐明。本研究观察到施万细胞（Schwann cell）分化过程中染色质可及性整体降低，并证实染色质组织者CCCTC结合因子（CCCTC-binding factor, CTCF）在神经损伤后施万细胞的髓鞘形成及髓鞘再生过程中发挥关键作用。抑制Ctcf基因表达或敲除Ctcf会使施万细胞分化阻滞于髓鞘形成前阶段，而过表达CTCF则可促进髓鞘形成程序。CTCF可在启动子与调控元件之间建立染色质相互作用环，以促进EGR2等关键促髓鞘形成因子的表达。此外，CTCF可与多梳抑制复合体2（polycomb-repressive-complex 2）的组分SUZ12相互作用，从而抑制HES1、RSPO2及CALCA等未成熟施万细胞相关调控因子的表达。综上，本研究结果揭示了依赖CTCF的染色质组织的双重功能：一方面促进髓鞘形成程序，另一方面招募染色质抑制复合体以阻断分化抑制因子，进而调控外周髓鞘形成与髓鞘修复。