Effects And Mechanism Study Of CTCF In Regulating Schwann Cell Differentiation And Peripheral Myelin Regeneration

Peripheral demyelinating diseases include rare disorders induced by inflammation,genetic and direct damage to peripheral nerve caused by trauma and toxin exposure,leading to serious consequences such as amputation and renal failure.The main clinical approach to relieving the disease is to alleviate the cause of the disease,but there is no good treatment for remyelination.Therefore,finding new therapeutic agents that can promote remyelination has become an urgent clinical problem.Schwann cells are peripheral myelin-forming cells that support and promote nerve impulse conduction,while after demyelination,SC proliferate and migrate to the lesion,subsequently dedifferentiate to form myelin sheaths,suggesting that SC may serve as a target cell for the treatment of peripheral demyelinating diseases.Recent studies have shown that chromatin remodeling is critical for cell growth and differentiation,however,its function in peripheral myelination and myelin repair remain elusive.In this study,we demonstrate that the CCCTC-binding factor(CTCF),a crucial chromatin organizer,is essential for SC myelination and myelin regeneration after nerve injury,as well as its specific mechanism.Herein,we find for the first time that CTCF expression is increased during SC development,inhibition of CTCF or its deletion blocks SC differentiation at the promyelinating stage.Apart from that,CTCF promotes SC dedifferentiation and remyelination after peripheral nerve injury.We find that CTCF establishes chromatin interaction loops between enhancer and promoter regulatory elements and promotes expression of a key pro-myelinogenic factor Early Growth Response Protein 2(EGR2).In addition,CTCF interacts with SUZ12 Polycomb Repressive Complex 2 Subunit(SUZ12),a component of Polycomb Repressive Complex2(PRC2),to repress the transcriptional program associated with negative regulation of SC maturation.Together,our findings reveal a dual role of CTCF-dependent chromatin organization in promoting myelinogenic programs and recruiting chromatin-repressive complexes to block SC differentiation inhibitors to control peripheral myelination and repair,our findings also provide a new strategy for the intervention of Schwann cells in the treatment of peripheral demyelinating diseases.