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Abnormal level of CUL4B-mediated histone H2A ubiquitination causes disruptive HOX gene expression
Epigenetics & Chromatin ( IF 4.2 ) Pub Date : 2019-04-16 , DOI: 10.1186/s13072-019-0268-7
Ye Lin , Juan Yu , Jianxin Wu , Shan Wang , Ting Zhang

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.

中文翻译:

CUL4B介导的组蛋白H2A泛素化水平异常导致破坏性HOX基因表达

神经管缺陷(NTD)是涉及中枢神经系统的常见先天性缺陷。关于人类NTD病因的最新研究提出了表观遗传调控可能参与确定其易感性的可能性。在这里,我们显示H2AK119ub1 E3连接酶CUL4B是NT2 / D1胚胎癌细胞中视黄酸(RA)诱导型发育关键同源盒(HOX)基因激活所必需的。RA处理由于CUL4B的减少而导致H2AK119ub1的减弱,从而进一步影响HOX基因的调控。此外,我们发现CUL4B直接与RORγ相互作用,并对其RORγ的转录活性产生负调控。有趣的是,在N2 / D1细胞的HOX基因位点,敲除RORγ会降低HOX基因的表达,并增加H2AK119ub1的占用水平。此外,在小鼠和人类无脑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,在人类无脑NTD病例中,HOXA10基因的表达与CUL4B水平呈负相关。我们的结果表明,异常的CUL4B介导的H2AK119ub1水平诱导的HOX基因表达异常可能是NTD的危险因素,并强调需要进一步分析NTD中的全基因组表观遗传修饰。
更新日期:2019-04-16
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