Folate deficiency induced H2A ubiquitination to lead to downregulated expression of genes involved in neural tube defects
Folate deficiency induced H2A ubiquitination to lead to downregulated expression of genes involved in neural tube defects
复制标题
叶酸缺乏诱导 H2A 泛素化，导致神经管缺陷相关基因表达下调
DOI：
10.1186/s13072-019-0312-7
复制
发表时间：
2019-11-13
影响因子：
3.9
通讯作者：
Zhang, Ting
中科院分区：
文献类型：
--
作者：
Pei, Pei;Cheng, Xiyue;Zhang, Ting
神经管缺陷（neural tube defects，NTDs）是胚胎发育早期神经管闭合失败的常见先天性畸形。虽然它是已知的，母亲叶酸缺乏增加NTDs的风险，机制仍然habitu.ResultsTherefore，我们报告组蛋白H2A monoubiquitination（H2AK119ub1）在神经管关闭中发挥作用。我们发现叶酸拮抗剂甲氨蝶呤在小鼠胚胎干细胞中诱导H2AK119ub1。我们证明了在叶酸缺乏的条件下，H2 AK119 ub1的增加下调了小鼠胚胎干细胞中神经管闭合相关基因Cdx 2、内斯、Pax 6和Gata 4的表达。我们还确定，E3连接酶Mdm 2负责蛋氨酸诱导的H2AK119ub1的增加和神经管关闭相关基因的下调。令人惊讶的是，我们发现Mdm 2是MTX诱导的H2A泛素化所必需的，并被招募到DSB的位点，这取决于DNA损伤信号激酶ATM。此外，补充叶酸恢复了H2AK119ub1与神经管闭合相关基因的结合。在小鼠和人NTD病例的脑组织中也观察到这些基因的下调，并且在相应的NTD样品中发现高水平的H2AK119ub1，其母体血清叶酸水平在低水平下。Pearson相关分析显示，神经前体基因的表达与H2AK119ub1呈显著负相关。结论叶酸缺乏可能通过改变H2AK119ub1的表达，进而影响神经管闭合相关基因的表达，从而导致神经管闭合障碍的发生。这可能是一个潜在的危险因素NTD在叶酸缺乏症。
BackgroundNeural tube defects (NTDs) are common congenital malformations resulting in failure of the neural tube closure during early embryonic development. Although it is known that maternal folate deficiency increases the risk of NTDs, the mechanism remains elusive.ResultsHerein, we report that histone H2A monoubiquitination (H2AK119ub1) plays a role in neural tube closure. We found that the folate antagonist methotrexate induced H2AK119ub1 in mouse embryonic stem cells. We demonstrated that an increase in H2AK119ub1 downregulated expression of the neural tube closure-related genesCdx2,Nes,Pax6, andGata4in mouse embryonic stem cells under folate deficiency conditions. We also determined that the E3 ligase Mdm2 was responsible for the methotrexate-induced increase in H2AK119ub1 and downregulation of neural tube closure-related genes. Surprisingly, we found that Mdm2 is required for MTX-induced H2A ubiquitination and is recruited to the sites of DSB, which is dependent on DNA damage signaling kinase ATM. Furthermore, folic acid supplementation restored H2AK119ub1 binding to neural tube closure-related genes. Downregulation of these genes was also observed in both brain tissue of mouse and human NTD cases, and high levels of H2AK119ub1 were found in the corresponding NTDs samples with their maternal serum folate under low levels. Pearson correlation analysis showed a significant negative correlation between expression of the neural precursor genes and H2AK119ub1.ConclusionOur results indicate that folate deficiency contributes to the onset of NTDs by altering H2AK119ub1 and subsequently affecting expression of neural tube closure-related genes. This may be a potential risk factor for NTDs in response to folate deficiency.