Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China.
Graduate Schools of Peking Union Medical College, Beijing, 100730, China.
Epigenetics Chromatin. 2019 Apr 16;12(1):22. doi: 10.1186/s13072-019-0268-7.
Neural tube defects (NTDs) are common birth defects involving the central nervous system. Recent studies on the etiology of human NTDs have raised the possibility that epigenetic regulation could be involved in determining susceptibility to them.
Here, we show that the H2AK119ub1 E3 ligase CUL4B is required for the activation of retinoic acid (RA)-inducible developmentally critical homeobox (HOX) genes in NT2/D1 embryonal carcinoma cells. RA treatment led to attenuation of H2AK119ub1 due to decrease in CUL4B, further affecting HOX gene regulation. Furthermore, we found that CUL4B interacted directly with RORγ and negatively regulated its transcriptional activity. Interestingly, knockdown of RORγ decreased the expression of HOX genes along with increased H2AK119ub1 occupancy levels, at HOX gene sites in N2/D1 cells. In addition, upregulation of HOX genes was observed along with lower levels of CUL4B-mediated H2AK119ub1 in both mouse and human anencephaly NTD cases. Notably, the expression of HOXA10 genes was negatively correlated with CUL4B levels in human anencephaly NTD cases.
Our results indicate that abnormal HOX gene expression induced by aberrant CUL4B-mediated H2AK119ub1 levels may be a risk factor for NTDs, and highlight the need for further analysis of genome-wide epigenetic modifications in NTDs.
神经管缺陷（NTDs）是一种常见的中枢神经系统先天缺陷。最近对人类 NTD 病因的研究提出了表观遗传调控可能参与决定易感性的可能性。
在这里，我们表明，H2AK119ub1 E3 连接酶 CUL4B 是 NT2/D1 胚胎癌细胞中视黄酸（RA）诱导的发育关键同源盒（HOX）基因激活所必需的。RA 处理导致由于 CUL4B 的减少而导致 H2AK119ub1 衰减，进一步影响 HOX 基因调节。此外，我们发现 CUL4B 与 RORγ 直接相互作用，并负调控其转录活性。有趣的是，RORγ 的敲低降低了 HOX 基因的表达，同时在 N2/D1 细胞中 HOX 基因位点上 H2AK119ub1 占据水平增加。此外，在鼠和人无脑畸形 NTD 病例中，均观察到 HOX 基因的上调以及 CUL4B 介导的 H2AK119ub1 水平降低。值得注意的是，HOXA10 基因的表达与人类无脑畸形 NTD 病例中的 CUL4B 水平呈负相关。
我们的结果表明，异常的 CUL4B 介导的 H2AK119ub1 水平引起的异常 HOX 基因表达可能是 NTD 的一个风险因素，并强调需要进一步分析 NTD 中的全基因组表观遗传修饰。
