Silencing of X-Linked MicroRNAs by Meiotic Sex Chromosome Inactivation.
During the pachytene stage of meiosis in male mammals, the X and Y chromosomes are transcriptionally silenced by Meiotic Sex Chromosome Inactivation (MSCI). MSCI is conserved in therian mammals and is essential for normal male fertility. Transcriptomics approaches have demonstrated that in mice, most or all protein-coding genes on the X chromosome are subject to MSCI. However, it is unclear whether X-linked non-coding RNAs behave in a similar manner. The X chromosome is enriched in microRNA (miRNA) genes, with many exhibiting testis-biased expression. Importantly, high expression levels of X-linked miRNAs (X-miRNAs) have been reported in pachytene spermatocytes, indicating that these genes may escape MSCI, and perhaps play a role in the XY-silencing process. Here we use RNA FISH to examine X-miRNA expression in the male germ line. We find that, like protein-coding X-genes, X-miRNAs are expressed prior to prophase I and are thereafter silenced during pachynema. X-miRNA silencing does not occur in mouse models with defective MSCI. Furthermore, X-miRNAs are expressed at pachynema when present as autosomally integrated transgenes. Thus, we conclude that silencing of X-miRNAs during pachynema in wild type males is MSCI-dependent. Importantly, misexpression of X-miRNAs during pachynema causes spermatogenic defects. We propose that MSCI represents a chromosomal mechanism by which X-miRNAs, and other potential X-encoded repressors, can be silenced, thereby regulating genes with critical late spermatogenic functions.
Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland; Swiss Institute of Bioinformatics, Basel, Switzerland; The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
Hélène
H
Royo
Institute of Human Genetics, UPR 1142, CNRS, Montpellier, France.
Hervé
H
Seitz
The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
Elias
E
ElInati
Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland.
Antoine H F M
AH
Peters
Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland; Swiss Institute of Bioinformatics, Basel, Switzerland.
Michael B
MB
Stadler
The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom.
James M A
JM
Turner
D000818:Animals; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D050172:Genes, X-Linked; D006801:Humans; D008297:Male; D008540:Meiosis / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D049471:Pachytene Stage; D013090:Spermatocytes / Q000378:metabolism; D013091:Spermatogenesis; D014960:X Chromosome / Q000235:genetics*; D049951:X Chromosome Inactivation / Q000235:genetics*; D014998:Y Chromosome / Q000235:genetics
D035683:MicroRNAs