Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis

Huanhuan Tan, Weixu Wang, Congjin Zhou, Yanfeng Wang, Shu Zhang, Pinglan Yang, Rui Guo, Wei Chen, Jinwen Zhang, Lan Ye, Yiqiang Cui (), Ting Ni () and Ke Zheng ()
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Huanhuan Tan: Nanjing Medical University
Weixu Wang: Human Phenome Institute, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences and Huashan Hospital, Fudan University
Congjin Zhou: Nanjing Medical University
Yanfeng Wang: Nanjing Medical University
Shu Zhang: Nanjing Medical University
Pinglan Yang: Nanjing Medical University
Rui Guo: Nanjing Medical University
Wei Chen: Human Phenome Institute, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences and Huashan Hospital, Fudan University
Jinwen Zhang: Nanjing Medical University
Lan Ye: Nanjing Medical University
Yiqiang Cui: Nanjing Medical University
Ting Ni: Human Phenome Institute, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences and Huashan Hospital, Fudan University
Ke Zheng: Nanjing Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Mammalian spermatogenesis shows prominent chromatin and transcriptomic switches in germ cells, but it is unclear how such dynamics are controlled. Here we identify RNA helicase DDX43 as an essential regulator of the chromatin remodeling process during spermiogenesis. Testis-specific Ddx43 knockout mice show male infertility with defective histone-to-protamine replacement and post-meiotic chromatin condensation defects. The loss of its ATP hydrolysis activity by a missense mutation replicates the infertility phenotype in global Ddx43 knockout mice. Single-cell RNA sequencing analyses of germ cells depleted of Ddx43 or expressing the Ddx43 ATPase-dead mutant reveals that DDX43 regulates dynamic RNA regulatory processes that underlie spermatid chromatin remodeling and differentiation. Transcriptomic profiling focusing on early-stage spermatids combined with enhanced crosslinking immunoprecipitation and sequencing further identifies Elfn2 as DDX43-targeted hub gene. These findings illustrate an essential role for DDX43 in spermiogenesis and highlight the single-cell-based strategy to dissect cell-state-specific regulation of male germline development.

Date: 2023
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DOI: 10.1038/s41467-023-38199-w

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