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CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

Author

Listed:
  • Jie Zhang

    (Chinese Academy of Sciences
    The First Affiliated Hospital of Guangzhou Medical University)

  • Gongcheng Hu

    (Guangzhou National Laboratory)

  • Yuli Lu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Huawei Ren

    (Shanxi Agricultural University)

  • Yin Huang

    (Guangzhou National Laboratory)

  • Yulin Wen

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Binrui Ji

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Diyang Wang

    (Jinan University)

  • Haidong Wang

    (Shanxi Agricultural University)

  • Huisheng Liu

    (Guangzhou National Laboratory)

  • Ning Ma

    (Guangzhou National Laboratory)

  • Lingling Zhang

    (Anhui Medical University)

  • Guangjin Pan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yibo Qu

    (Jinan University)

  • Hua Wang

    (Anhui Medical University)

  • Wei Zhang

    (Guangzhou National Laboratory)

  • Zhichao Miao

    (Guangzhou National Laboratory)

  • Hongjie Yao

    (Chinese Academy of Sciences
    The First Affiliated Hospital of Guangzhou Medical University
    Guangzhou National Laboratory
    University of Chinese Academy of Sciences)

Abstract

The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explore the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibit growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single-cell transcriptome levels. This mutation induces premature stem-like cell exhaustion, accelerates the maturation of GABAergic neurons, and disrupts neurodevelopmental and synaptic pathways. Additionally, it specifically hinders CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrors the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

Suggested Citation

  • Jie Zhang & Gongcheng Hu & Yuli Lu & Huawei Ren & Yin Huang & Yulin Wen & Binrui Ji & Diyang Wang & Haidong Wang & Huisheng Liu & Ning Ma & Lingling Zhang & Guangjin Pan & Yibo Qu & Hua Wang & Wei Zha, 2024. "CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49684-1
    DOI: 10.1038/s41467-024-49684-1
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