Widespread association of the Argonaute protein AGO2 with meiotic chromatin suggests a distinct nuclear function in mammalian male reproduction [RESEARCH]

Kimberly N. Griffin1,12, Benjamin William Walters1,12, Haixin Li1,12,13, Huafeng Wang2, Giulia Biancon3,4, Toma Tebaldi3,4,5, Carolyn B. Kaya1, Jean Kanyo6, TuKiet T. Lam6,7, Andy L. Cox1, Stephanie Halene3,4,8,9,10, Jean-Ju Chung2,11 and Bluma J. Lesch1,4,11 1Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA; 2Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA; 3Section of Hematology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA; 4Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA; 5Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38123 Trento, Italy; 6Keck MS & Proteomics Resource, Yale University School of Medicine, New Haven, Connecticut 06510, USA; 7Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520, USA; 8Yale Stem Cell Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA; 9Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA; 10Department of Pathology, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510, USA; 11Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06510, USA

12 These authors contributed equally to this work.

13 Present address: Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200092, China

Corresponding author: bluma.leschyale.edu Abstract

Argonaute 2 (AGO2) is a ubiquitously expressed protein critical for regulation of mRNA translation and vital to animal development. AGO2 protein is found in both cytoplasmic and nuclear compartments, and although its cytoplasmic role is well studied, the biological relevance of nuclear AGO2 is unclear. Here, we address this problem in vivo using spermatogenic cells as a model. We find that AGO2 transiently binds both chromatin and nucleus-specific mRNA transcripts of hundreds of genes required for sperm production during male meiosis in mice, and that germline conditional knockout (cKO) of Ago2 causes depletion of the encoded proteins. Correspondingly, Ago2 cKO males show abnormal sperm head morphology and reduced sperm count, along with reduced postnatal viability of offspring. Together, our data reveal an unexpected nuclear role for AGO2 in enhancing expression of developmentally important genes during mammalian male reproduction.

Received January 11, 2022. Accepted July 21, 2022.

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