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Phase-separated CCER1 coordinates the histone-to-protamine transition and male fertility

Author

Listed:
  • Dongdong Qin

    (Nanjing Medical University)

  • Yayun Gu

    (Nanjing Medical University
    Nanjing Medical University)

  • Yu Zhang

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences
    Fudan University
    Chinese Academy of Medical Sciences)

  • Shu Wang

    (Nanjing Medical University)

  • Tao Jiang

    (Nanjing Medical University
    Nanjing Medical University)

  • Yao Wang

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Cheng Wang

    (Nanjing Medical University
    Nanjing Medical University)

  • Chang Chen

    (Nanjing Medical University)

  • Tao Zhang

    (Nanjing Medical University)

  • Weiya Xu

    (Nanjing Medical University)

  • Hanben Wang

    (Nanjing Medical University)

  • Ke Zhang

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Liangjun Hu

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Lufan Li

    (Nanjing Medical University)

  • Wei Xie

    (Tsinghua University
    Tsinghua-Peking Center for Life Sciences)

  • Xin Wu

    (Nanjing Medical University)

  • Zhibin Hu

    (Nanjing Medical University
    Nanjing Medical University)

Abstract

Idiopathic fertility disorders are associated with mutations in various genes. Here, we report that coiled-coil glutamate-rich protein 1 (CCER1), a germline-specific and intrinsically disordered protein (IDP), mediates postmeiotic spermatid differentiation. In contrast, CCER1 deficiency results in defective sperm chromatin compaction and infertility in mice. CCER1 increases transition protein (Tnp1/2) and protamine (Prm1/2) transcription and mediates multiple histone epigenetic modifications during the histone-to-protamine (HTP) transition. Immiscible with heterochromatin in the nucleus, CCER1 self-assembles into a polymer droplet and forms a liquid-liquid phase-separated condensate in the nucleus. Notably, we identified loss-of-function (LoF) variants of human CCER1 (hCCER1) in five patients with nonobstructive azoospermia (NOA) that were absent in 2713 fertile controls. The mutants led to premature termination or frameshift in CCER1 translation, and disrupted condensates in vitro. In conclusion, we propose that nuclear CCER1 is a phase-separated condensate that links histone epigenetic modifications, HTP transitions, chromatin condensation, and male fertility.

Suggested Citation

  • Dongdong Qin & Yayun Gu & Yu Zhang & Shu Wang & Tao Jiang & Yao Wang & Cheng Wang & Chang Chen & Tao Zhang & Weiya Xu & Hanben Wang & Ke Zhang & Liangjun Hu & Lufan Li & Wei Xie & Xin Wu & Zhibin Hu, 2023. "Phase-separated CCER1 coordinates the histone-to-protamine transition and male fertility," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43480-z
    DOI: 10.1038/s41467-023-43480-z
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    References listed on IDEAS

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