中枢神经系统(CNS)脱髓鞘是多种神经系统疾病的重要病理特征，研究CNS髓鞘形成细胞—少突胶质细胞(OL)的分化成熟机制对促进再髓鞘化非常重要。近年来表观遗传调控在OL发育中的作用逐渐受到重视。我们前期观察到，一种氧合酶家族分子—TET1在少突前体和未成熟细胞中高表达，且在OL中条件性敲除该分子(TET1CKO)将影响细胞谱系形成和早期分化。但作为TET的催化产物—DNA羟甲基胞嘧啶(5-hmc)，在少突前体细胞中修饰水平较低。因此我们推测TET1可能通过非5-hmc修饰依赖的方式调控相关靶基因的表达并促进OL谱系形成。我们计划利用TET1CKO小鼠，从TET1在OL基因组中结合的靶基因入手，探讨三种TET1可能参与的转录调控复合物对相应靶基因的调控作用，并验证靶基因对OL分化的影响。本研究将为全面认识少突分化的调控机制提供崭新的思路，并为促进髓鞘缺失疾病的成功再髓鞘化提供重要的实验依据。

Demyelination in the central nervous system (CNS) is associated with many demyelinating disorders and nervous system injury. Oligodendrocyte (OL) is the only myelinating cell in the CNS and the failure of OL remyelination impairs rapid propagation of action potentials and leads to nerve degeneration. To promote remyelination, it is important to understand the mechanism for OL differentiation. Epigenetic modification has been identified as an important player in the regulation of OL differentiation. Recently, we have identified the expression of TET dioxygenase family members during OL differentiation, in which three members show different pattern and TET1 is highly expressed in oligodendrocyte precursor cells (OPCs) and early differentiated immature OL. In TET1 conditional knockout mice (TET1 loxP/loxP; Olig1-cre, TET1 CKO), which loss TET1 function in OL lineage, the specification and early differentiation of OL are repressed. But, as the product of TET dioxygenase, 5-hydroxymethylcytosine (5-hmc) level starts to rise from immature OLs and therefore is thought to be involved in later maturation of OL. These observations suggest that the stage-specific appearance of TET1 might regulate certain target genes expression through 5-hmc independent ways. With the facility of TET1CKO mice, we plan to map the target genes of TET1 in OLs and study the chromatin regulator complexes that TET1 might involve in, especially TET1/Ezh2, TET1/Sin3A/HDAC and TET1/OGT/HCF1/SET/COMPASS. After confirming the regulatory role of these complexes in the expression of TET1 target genes, we will overexpress or knockdown target genes in TET1CKO embryo or OL cultures to test the rescue effect in OL lineage formation and early differentiation. This study reveals a new epigenetic category in understanding OL differentiation and might be applied in further study on promoting remyelination in CNS related diseases.