Neural zinc finger protein Myt1 drives oligodendrocyte differentiation via repressing HDAC1-mediated histone deacetylation [H3K9 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. In light of our findings that loss of Myt1 expression delayed OL differentiation, we sought to identify Myt1-regulated downstream target genes by RNA-sequencing (RNA-seq) in mouse P0 Myt1-/- and wild type spinal cords

髓鞘转录因子（myelin transcription factor, Myt）家族成员已被证实参与神经元发育过程。然而，该家族成员在少突胶质细胞（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。常规Myt1基因敲除会显著延缓少突胶质细胞分化的起始进程，但不影响少突胶质细胞前体细胞（oligodendrocyte progenitor 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。通过RNA测序（RNA-seq）与染色质免疫共沉淀测序（ChIP-seq）的联合分析，我们鉴定出Nkx2.2是Myt1激活少突胶质细胞分化程序的关键靶基因。从机制来看，Myt1在Nkx2.2基因位点的特异性结合，可通过阻碍组蛋白去乙酰化酶1（histone deacetylase 1, HDAC1）阻遏复合物的完整性、降低HDAC1的去乙酰化活性，从而抑制核小体组蛋白去乙酰化。此外，我们证实Myt1在调控少突胶质细胞分化时序的过程中，作用于Notch信号通路的下游。综上，本研究数据表明Myt1是少突胶质细胞分化的核心调控因子，并为少突胶质细胞发育的表观遗传调控机制提供了新的研究视角。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与髓鞘形成/髓鞘修复的潜在治疗靶点。鉴于我们发现Myt1表达缺失会延缓少突胶质细胞分化，我们通过对小鼠出生后0天（postnatal day 0, P0）Myt1基因敲除型（Myt1-/-）与野生型脊髓组织开展RNA测序（RNA-seq），旨在鉴定Myt1调控的下游靶基因。