Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects

Qin Zhang, Baoling Bai, Xinyu Mei, Chunlei Wan, Haiyan Cao, Li, Shan Wang, Min Zhang, Zhigang Wang, Jianxin Wu, Hongyan Wang, Junsheng Huo, Gangqiang Ding, Jianyuan Zhao, Qiu Xie, Li Wang, Zhiyong Qiu, Shiming Zhao () and Ting Zhang ()
Additional contact information
Qin Zhang: Capital Institute of Pediatrics
Baoling Bai: Capital Institute of Pediatrics
Xinyu Mei: Engineering and Institutes of Biomedical Sciences
Chunlei Wan: Capital Institute of Pediatrics
Haiyan Cao: Capital Institute of Pediatrics
Li: Capital Institute of Pediatrics
Shan Wang: Capital Institute of Pediatrics
Min Zhang: Capital Institute of Pediatrics
Zhigang Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Jianxin Wu: Capital Institute of Pediatrics
Hongyan Wang: Engineering and Institutes of Biomedical Sciences
Junsheng Huo: Chinese Center for Disease Control and Prevention
Gangqiang Ding: Chinese Center for Disease Control and Prevention
Jianyuan Zhao: Fudan University
Qiu Xie: Chinese Academy of Medical Sciences & Peking Union Medical College
Li Wang: Capital Institute of Pediatrics
Zhiyong Qiu: Capital Institute of Pediatrics
Shiming Zhao: Engineering and Institutes of Biomedical Sciences
Ting Zhang: Capital Institute of Pediatrics

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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 including Cecr2, Smarca4, and Dnmt3b. In human NTDs brain tissues, decrease in expression of CECR2, SMARCA4, and DNMT3B is 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.

Date: 2018
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DOI: 10.1038/s41467-018-05451-7

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