Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects
Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects
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H3K79 高半胱氨酸化导致神经发育过程中基因表达异常以及随后的神经管缺陷
DOI：
10.1038/s41467-018-05451-7
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发表时间：
2018-08
影响因子：
16.6
通讯作者：
Zhang Ting
中科院分区：
文献类型：
--
作者：
Zhang Qin;Bai Baoling;Mei Xinyu;Wan Chunlei;Cao Haiyan;Li Dan;Wang Shan;Zhang Min;Wang Zhigang;Wu Jianxin;Wang Hongyan;Huo Junsheng;Ding Gangqiang;Zhao Jianyuan;Xie Qiu;Wang Li;Qiu Zhiyong;Zhao Shiming;Zhang Ting
神经管缺损是一种严重的先天性畸形。过量的母体同型半胱氨酸（Hcy）增加了被忽视热带病的风险，而其机制尚不清楚。在这里，我们报告了组蛋白同型半胱氨酸化在神经管闭合（NTC）中的作用。用质谱法在人胚胎脑组织样品中鉴定了39个组蛋白同型半胱氨酸化位点。组蛋白KHcy和H3K79Hcy水平升高是在人类胎儿大脑细胞Hcy水平升高时检测到的。通过ChIP-seq和RNA-seq分析，我们发现H3K79Hcy水平的升高下调了选定的ntc相关基因的表达，包括cecr2、Smarca4和dnmt3b。在人类NTDs脑组织中，cecr2、SMARCA4和dnmt3bis的表达也下降，Hcy和H3K79Hcy水平也升高。我们的研究结果表明，高水平的Hcy通过上调组蛋白H3K79Hcy，导致ntc相关基因的异常表达，从而促进了ntd的发病。
Neural tube defects (NTDs) are serious congenital malformations. Excessive maternal homocysteine (Hcy) increases the risk of NTDs, while its mechanism remains elusive. Here we report the role of histone homocysteinylation in neural tube closure (NTC). A total of 39 histone homocysteinylation sites are identified in samples from human embryonic brain tissue using mass spectrometry. Elevated levels of histone KHcy and H3K79Hcy are detected at increased cellular Hcy levels in human fetal brains. Using ChIP-seq and RNA-seq assays, we demonstrate that an increase in H3K79Hcy level down-regulates the expression of selected NTC-related genes includingCecr2,Smarca4, andDnmt3b. In human NTDs brain tissues, decrease in expression ofCECR2, SMARCA4,andDNMT3Bis also detected along with high levels of Hcy and H3K79Hcy. Our results suggest that higher levels of Hcy contribute to the onset of NTDs through up-regulation of histone H3K79Hcy, leading to abnormal expressions of selected NTC-related genes.
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影响因子：
2.7
作者：
Glasco, Derrick M.;Sittaramane, Vinoth;Bryant, Whitney;Fritzsch, Bernd;Sawant, Anagha;Paudyal, Anju;Stewart, Michelle;Andre, Philipp;Vilhais-Neto, Goncalo Cadete;Yang, Yingzi;Song, Mi-Ryoung;Murdoch, Jennifer N.;Chandrasekhar, Anand
通讯作者：
Chandrasekhar, Anand
影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
影响因子：
5.2
作者：
Mentch SJ;Locasale JW
通讯作者：
Locasale JW
DOI：
10.1002/tera.1420500506
发表时间：
1994-11
期刊：
Teratology
影响因子：
--
作者：
L. A. Vanaerts;Henk J. Blom;Ronney A. Deabreu;Frans J. M. Trijbels;T. Eskes;Jenny H.J. Copius Peereboom-Stegeman;Jan Noordhoek
通讯作者：
L. A. Vanaerts;Henk J. Blom;Ronney A. Deabreu;Frans J. M. Trijbels;T. Eskes;Jenny H.J. Copius Peereboom-Stegeman;Jan Noordhoek
影响因子：
64.5
作者：
Huang H;Sabari BR;Garcia BA;Allis CD;Zhao Y
通讯作者：
Zhao Y