Neural zinc finger protein Myt1 drives oligodendrocyte differentiation via repressing HDAC1-mediated histone deacetylation [MYT ChIP-seq]

Members of the Myt (myelin transcription factor) family have been implicated in neuronal development. However, their in vivo roles in OL lineage development have not been systematically investigated. Here, we identified Myt1 transcription factor as a crucial regulator of oligodendrocyte differentiation in the developing central nervous system. Conventional knockout of Myt1 causes a remarkable delay in the initiation of OL differentiation, without affecting the generation and proliferation of OPCs. Conversely, hyperactivation of Myt1 induces precocious OL differentiation both in vitro and in vivo. Using a combination of RNA-seq and ChIP-seq analyses, we identified Nkx2.2 as a key target of Myt1 to switch on the OL differentiation program. Mechanistically, specific binding of Myt1 in the Nkx2.2 gene loci inhibits the nucleosomal histone deacetylation via hindering the HDAC1 repressor complex integrity and reducing the deacetylation activity of HDAC1. Additionally, we demonstrated that Myt1 functions downstream of Notch signaling pathway in controlling the timing of OL differentiation. Collectively, our data demonstrate that Myt1 is a major regulator of OL differentiation and provide insight into the epigenetic regulatory mechanisms under OL development. Myt1 is, therefore, a promising therapeutic target for enhancing the OL differentiation and myelination/remyelination during development or after demyelination insults.髓鞘转录因子（myelin transcription factor, Myt）家族成员已被证实与神经元发育相关。然而，其在少突胶质细胞（oligodendrocyte, OL）谱系发育中的体内功能尚未得到系统研究。本研究中，我们鉴定出Myt1转录因子是发育中中枢神经系统内少突胶质细胞分化的关键调控因子。传统的Myt1基因敲除会显著延迟少突胶质细胞分化的起始过程，且不影响少突胶质前体细胞（oligodendrocyte precursor cell, OPC）的产生与增殖。反之，Myt1的过度激活可在体外与体内诱导少突胶质细胞提前分化。结合RNA测序（RNA-seq）与染色质免疫沉淀测序（ChIP-seq）分析，我们鉴定出Nkx2.2是Myt1启动少突胶质细胞分化程序的关键靶基因。机制层面，Myt1在Nkx2.2基因位点的特异性结合，通过阻碍组蛋白去乙酰化酶1（HDAC1）阻遏复合物的完整性并降低其去乙酰化活性，抑制核小体组蛋白的去乙酰化过程。此外，我们证实Myt1在Notch信号通路下游调控少突胶质细胞分化的时序。综上，我们的研究数据表明Myt1是少突胶质细胞分化的核心调控因子，并为解析少突胶质细胞发育的表观遗传调控机制提供了新视角。因此，Myt1有望成为在发育阶段或脱髓鞘损伤后促进少突胶质细胞分化以及髓鞘形成/再髓鞘化的潜在治疗靶点。