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Nat Commun. 2018 Aug 24;9(1):3436. doi: 10.1038/s41467-018-05451-7.

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

Author information

1
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, Beijing, China.
2
Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic, Engineering and Institutes of Biomedical Sciences, 200433, Shanghai, China.
3
Weifang Medical University, 261053, Weifang, China.
4
Chinese Academy of Medical Sciences & Peking Union Medical College, 100005, Beijing, China.
5
Key Laboratory of Trace Element Nutrition of National Health and Family Planning Commission of the People's Republic of China, National Institute for Nutrition and Health, Chinese Center for Disease Control and Prevention, 102206, Beijing, China.
6
State Key Laboratory of Genetic Engineering and School of Life Sciences, Fudan University, 200438, Shanghai, China.
7
Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic, Engineering and Institutes of Biomedical Sciences, 200433, Shanghai, China. zhaosm@fudan.edu.cn.
8
Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, 100020, Beijing, China. Zhangtingcv@126.com.

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.

PMID:
30143612
PMCID:
PMC6109101
DOI:
10.1038/s41467-018-05451-7
[Indexed for MEDLINE]
Free PMC Article

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