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

Author

Listed:
  • 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
    Weifang Medical University)

  • 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)

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.

Suggested Citation

  • 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 Wa, 2018. "Elevated H3K79 homocysteinylation causes abnormal gene expression during neural development and subsequent neural tube defects," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05451-7
    DOI: 10.1038/s41467-018-05451-7
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