Ren Xinyue, Yang Ying, Wang Min, Yuan Qianting, Suo Na, Xie Xin
State Key Laboratory of Drug Research, National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China.
Molecules. 2024 Dec 16;29(24):5939. doi: 10.3390/molecules29245939.
DNA methylation and demethylation are key epigenetic events that regulate gene expression and cell fate. DNA demethylation via oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) is typically mediated by TET (ten-eleven translocation) enzymes. The 5hmC modification is considered an intermediate state of DNA demethylation; it is particularly prevalent in the brain and is believed to play a role in the development of many cell types in the brain. Our previous studies have identified that vitamin C (Vc) and MEK inhibitor PD0325901 could significantly promote OPC (oligodendrocyte progenitor cell)-to-OL (oligodendrocyte) differentiation. Here we discovered that Vc and PD0325901 may promote OPC-to-OL differentiation by inducing DNA demethylation via hydroxymethylation. Blocking 5hmC formation almost totally blocked Vc- and PD0325901-stimulated OPC-to-OL differentiation. In addition, TET1 is not involved in Vc,- and PD0325901-promoted OL generation. We also found a synergistic effect between the two compounds in inducing OL generation, suggesting the possibility of a combination therapy for demyelination diseases in the future.
DNA甲基化和去甲基化是调控基因表达和细胞命运的关键表观遗传事件。通过将5-甲基胞嘧啶（5mC）氧化为5-羟甲基胞嘧啶（5hmC）实现的DNA去甲基化通常由TET（十一-易位）酶介导。5hmC修饰被认为是DNA去甲基化的中间状态；它在大脑中特别普遍，并且被认为在大脑中许多细胞类型的发育中起作用。我们之前的研究已经确定，维生素C（Vc）和MEK抑制剂PD0325901可以显著促进少突胶质前体细胞（OPC）向少突胶质细胞（OL）的分化。在这里，我们发现Vc和PD0325901可能通过诱导羟甲基化导致的DNA去甲基化来促进OPC向OL的分化。阻断5hmC的形成几乎完全阻断了Vc和PD0325901刺激的OPC向OL的分化。此外，TET1不参与Vc和PD0325901促进的OL生成。我们还发现这两种化合物在诱导OL生成方面具有协同作用，这表明未来可能存在针对脱髓鞘疾病的联合治疗方法。
