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journal article·2024-09Open access

HSF5 Deficiency Causes Male Infertility Involving Spermatogenic Arrest at Meiotic Prophase I in Humans and Mice

Mohan Liu, Lingbo Wang, Yifei Li, Erlei Zhi, Gan Shen, Xiaohui Jiang, Dingming Li, Xinya Zhao, Tiechao Ruan, Chuan Jiang, Xiang Wang, Xueguang Zhang, Yanjiang Zheng, Bangguo Wu, Ningjing Ou, Guicheng Zhao, Siyu Dai, Ruixi Zhou, Li Yang, Yihong Yang, Hanmin Liu, Ying Shen

Advanced Science· Volume 11· Issue 33
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Source abstract

Abstract

Abstract Meiosis is a specialized cell division process that generates gametes for sexual reproduction. However, the factors and underlying mechanisms involving meiotic progression remain largely unknown, especially in humans. Here, it is first showed that HSF5 is associated with human spermatogenesis. Patients with a pathogenic variant of HSF5 are completely infertile. Testicular histologic findings in the patients reveal rare postmeiotic germ cells resulting from meiotic prophase I arrest. Hsf5 knockout (KO) mice confirms that the loss of HSF5 causes defects in meiotic recombination, crossover formation, sex chromosome synapsis, and sex chromosome inactivation (MSCI), which may contribute to spermatocyte arrest at the late pachytene stage. Importantly, spermatogenic arrest can be rescued by compensatory HSF5 adeno‐associated virus injection into KO mouse testes. Mechanistically, integrated analysis of RNA sequencing and chromatin immunoprecipitation sequencing data revealed that HSF5 predominantly binds to promoters of key genes involved in crossover formation (e.g., HFM1, MSH5 and MLH3), synapsis (e.g., SYCP1, SYCP2 and SYCE3), recombination (TEX15), and MSCI (MDC1) and further regulates their transcription during meiotic progression. Taken together, the study demonstrates that HSF5 modulates the transcriptome to ensure meiotic progression in humans and mice. These findings will aid in genetic diagnosis of and potential treatments for male infertility.
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Research context

OpenAlex topics: Sperm and Testicular Function · Heat shock proteins research · Reproductive Biology and Fertility

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Obstetrics/Gynecology Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education West China Second University Hospital Sichuan University Chengdu 610041 China

Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China

Shanghai Key Laboratory of Metabolic Remodeling and Health Institute of Metabolism and Integrative Biology Institute of Reproduction and Development Obstetrics and Gynecology Hospital Fudan University Shanghai 200433 China

Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE Department of Pediatrics West China Second University Hospital Sichuan University Chengdu 610041 China

Urology Urologic Medical Center Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200000 China

Human Sperm Bank Key Laboratory of Birth Defects and Related Diseases of Women and Children Ministry of Education West China Second University Hospital Sichuan University Chengdu 610041 China

NHC Key Laboratory of Chronobiology Sichuan University Chengdu 610041 China

West China School of preclinical medicine and forensic medicine Sichuan University Chengdu 610041 China

Department of Pediatrics West China Second University Hospital Sichuan University Chengdu 610041 China

Department of Urology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 China

Department of Pediatric Pulmonology and Immunology West China Second University Hospital Sichuan University Chengdu 610041 China

Reproduction Medical Center of West China Second University Hospital Key Laboratory of Obstetric Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education Sichuan University Chengdu 610041 China

Funding

West China Hospital, Sichuan University · Sichuan University · Health and Family Planning Commission of Sichuan Province

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