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

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 () and Zhibin Hu ()
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Dongdong Qin: Nanjing Medical University
Yayun Gu: Nanjing Medical University
Yu Zhang: Tsinghua University
Shu Wang: Nanjing Medical University
Tao Jiang: Nanjing Medical University
Yao Wang: Tsinghua University
Cheng Wang: 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
Liangjun Hu: Tsinghua University
Lufan Li: Nanjing Medical University
Wei Xie: Tsinghua University
Xin Wu: Nanjing Medical University
Zhibin Hu: Nanjing Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43480-z

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