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RNA polymerase II pausing is essential during spermatogenesis for appropriate gene expression and completion of meiosis

Author

Listed:
  • Emily G. Kaye

    (Harvard Medical School)

  • Kavyashree Basavaraju

    (University of Illinois Urbana-Champaign)

  • Geoffrey M. Nelson

    (Harvard Medical School)

  • Helena D. Zomer

    (University of Illinois Urbana-Champaign)

  • Debarun Roy

    (University of Illinois Urbana-Champaign)

  • Irene Infancy Joseph

    (University of Illinois Urbana-Champaign)

  • Reza Rajabi-Toustani

    (University of Illinois Urbana-Champaign)

  • Huanyu Qiao

    (University of Illinois Urbana-Champaign)

  • Karen Adelman

    (Harvard Medical School)

  • Prabhakara P. Reddi

    (University of Illinois Urbana-Champaign)

Abstract

Male germ cell development requires precise regulation of gene activity in a cell-type and stage-specific manner, with perturbations in gene expression during spermatogenesis associated with infertility. Here, we use steady-state, nascent and single-cell RNA sequencing strategies to comprehensively characterize gene expression across male germ cell populations, to dissect the mechanisms of gene control and provide new insights towards therapy. We discover a requirement for pausing of RNA Polymerase II (Pol II) at the earliest stages of sperm differentiation to establish the landscape of gene activity across development. Accordingly, genetic knockout of the Pol II pause-inducing factor NELF in immature germ cells blocks differentiation to spermatids. Further, we uncover unanticipated roles for Pol II pausing in the regulation of meiosis during spermatogenesis, with the presence of paused Pol II associated with double-strand break (DSB) formation, and disruption of meiotic gene expression and DSB repair in germ cells lacking NELF.

Suggested Citation

  • Emily G. Kaye & Kavyashree Basavaraju & Geoffrey M. Nelson & Helena D. Zomer & Debarun Roy & Irene Infancy Joseph & Reza Rajabi-Toustani & Huanyu Qiao & Karen Adelman & Prabhakara P. Reddi, 2024. "RNA polymerase II pausing is essential during spermatogenesis for appropriate gene expression and completion of meiosis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45177-3
    DOI: 10.1038/s41467-024-45177-3
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    1. Jiexiang Zhao & Ping Lu & Cong Wan & Yaping Huang & Manman Cui & Xinyan Yang & Yuqiong Hu & Yi Zheng & Ji Dong & Mei Wang & Shu Zhang & Zhaoting Liu & Shuhui Bian & Xiaoman Wang & Rui Wang & Shaofang , 2021. "Cell-fate transition and determination analysis of mouse male germ cells throughout development," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    2. Adriana K. Alexander & Edward J. Rice & Jelena Lujic & Leah E. Simon & Stephanie Tanis & Gilad Barshad & Lina Zhu & Jyoti Lama & Paula E. Cohen & Charles G. Danko, 2023. "A-MYB and BRDT-dependent RNA Polymerase II pause release orchestrates transcriptional regulation in mammalian meiosis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Christina Ernst & Nils Eling & Celia P. Martinez-Jimenez & John C. Marioni & Duncan T. Odom, 2019. "Staged developmental mapping and X chromosome transcriptional dynamics during mouse spermatogenesis," Nature Communications, Nature, vol. 10(1), pages 1-20, December.
    4. Seychelle M. Vos & Lucas Farnung & Marc Boehning & Christoph Wigge & Andreas Linden & Henning Urlaub & Patrick Cramer, 2018. "Structure of activated transcription complex Pol II–DSIF–PAF–SPT6," Nature, Nature, vol. 560(7720), pages 607-612, August.
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