Abnormal level of CUL4B-mediated histone H2A ubiquitination causes disruptive HOX gene expression
Abnormal level of CUL4B-mediated histone H2A ubiquitination causes disruptive HOX gene expression
复制标题
CUL4B 介导的组蛋白 H2A 泛素化水平异常导致 HOX 基因表达破坏
DOI：
10.1186/s13072-019-0268-7
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发表时间：
2019-04-16
影响因子：
3.9
通讯作者：
Zhang, Ting
中科院分区：
文献类型：
--
作者：
Lin, Ye;Yu, Juan;Zhang, Ting
背景神经管缺陷（Neural tube defects，NTDs）是一种常见的中枢神经系统缺陷.最近的研究对人类NTDs的病因提出了可能性，表观遗传调控可能参与确定易感themes.ResultsHere，我们表明，H2 AK 119 ub 1 E3连接酶CUL 4 B是必需的维甲酸（RA）诱导的发育关键同源异型盒（HOX）基因在NT 2/D1胚胎癌细胞的激活。RA处理导致H2 AK 119 ub 1由于CUL 4 B减少而减弱，进一步影响HOX基因调控。此外，我们发现CUL 4 B直接与RORγ相互作用，并负调控其转录活性。有趣的是，在N2/D1细胞中，RORγ的敲低降低了HOX基因的表达，同时沿着H2 AK 119 ub 1占据水平的增加。此外，在小鼠和人无脑畸形NTD病例中观察到HOX基因的上调沿着较低水平的CUL 4 B介导的H2 AK 119 ub 1。值得注意的是，HOXA 10基因的表达呈负相关，与CUL 4 B水平在人类无脑NTDcases.ConclusionsOur结果表明，异常的HOX基因表达诱导的异常CUL 4 B介导的H2 AK 119 ub 1水平可能是NTDs的一个危险因素，并强调需要进一步分析的全基因组表观遗传修饰NTDs。
BackgroundNeural 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.ResultsHere, 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.ConclusionsOur 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.