Journal
BIOLOGY OF REPRODUCTION
Volume 97, Issue 2, Pages 313-323Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/biolre/iox084
Keywords
meiosis; spermatogenesis; epigenetics; lncRNAs; CRISPR/Cas9
Categories
Funding
- March of Dimes grant [1-FY14-234]
- Clinical and Translational Science Collaborative of Cleveland from the National Center for Advancing Translational Sciences (NCATS) [UL1TR000439]
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Mammalian reproduction requires that males and females produce functional haploid germ cells through complex cellular differentiation processes known as spermatogenesis and oogenesis, respectively. While numerous studies have functionally characterized protein-coding genes and small noncoding RNAs (microRNAs and piRNAs) that are essential for gametogenesis, the roles of regulatory long noncoding RNAs (lncRNAs) are yet to be fully characterized. Previously, we and others have demonstrated that intergenic regions of the mammalian genome encode thousands of long noncoding RNAs, and many studies have now demonstrated their critical roles in key biological processes. Thus, we postulated that some lncRNAs may also impact mammalian spermatogenesis and fertility. In this study, we identified a dynamic expression pattern of lncRNAs during murine spermatogenesis. Importantly, we identified a subset of lncRNAs and very few mR-NAs that appear to escape meiotic sex chromosome inactivation, an epigenetic process that leads to the silencing of the X-and Y-chromosomes at the pachytene stage of meiosis. Further, some of these lncRNAs and mRNAs show a strong testis expression pattern suggesting that they may play key roles in spermatogenesis. Lastly, we generated a mouse knockout of one X-linked IncRNA, Tslrn1 (testis-specific long noncoding RNA 1), and found that males carrying a Tslrn1 deletion displayed normal fertility but a significant reduction in spermatozoa. Our findings demonstrate that dysregulation of specific mammalian lncRNAs is a novel mechanism of low sperm count or infertility, thus potentially providing new biomarkers and therapeutic strategies. Summary Sentence Long non-coding RNAs are critical for mammalian spermatogenesis.
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