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

Emily G. Kaye, Kavyashree Basavaraju, Geoffrey M. Nelson, Helena D. Zomer, Debarun Roy, Irene Infancy Joseph, Reza Rajabi-Toustani, Huanyu Qiao, Karen Adelman () and Prabhakara P. Reddi ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45177-3

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