Abstract
Meiosis requires conserved transcriptional changes, but it is not known whether there is a corresponding set of RNA splicing switches. Here, we used RNAseq of mouse testis to identify changes associated with the progression from mitotic spermatogonia to meiotic spermatocytes. We identified ∼150 splicing switches, most of which affect conserved protein-coding exons. The expression of many key splicing regulators changed in the course of meiosis, including downregulation of polypyrimidine tract binding protein (PTBP1) and heterogeneous nuclear RNP A1, and upregulation of nPTB, Tra2β, muscleblind, CELF proteins, Sam68 and T-STAR. The sequences near the regulated exons were significantly enriched in target sites for PTB, Tra2β and STAR proteins. Reporter minigene experiments investigating representative exons in transfected cells showed that PTB binding sites were critical for splicing of a cassette exon in the Ralgps2 mRNA and a shift in alternative 5′ splice site usage in the Bptf mRNA. We speculate that nPTB might functionally replace PTBP1 during meiosis for some target exons, with changes in the expression of other splicing factors helping to establish meiotic splicing patterns. Our data suggest that there are substantial changes in the determinants and patterns of alternative splicing in the mitotic-to-meiotic transition of the germ cell cycle.
Highlights
Most mammalian protein-coding genes are comprised of multiple exons and introns
As the use of many splice sites and alternative promoters or polyadenylation sites is regulated in response to extracellular cues or during development, alternative mRNA isoforms can determine the functions of a gene in different circumstances
For the Nasp and Odf2 genes, we found that that distinct transcriptional initiation sites were used in meiosis
Summary
Introns are generally much longer than exons and are removed from the initial transcript by pre-mRNA splicing. In $90% of genes, multiple mRNA isoforms are produced as a result of either the existence of multiple splicing pathways (alternative splicing) or the use of different promoters or termination sites [1,2,3]. Each human protein coding gene produces an average of 11 mRNA isoforms through alternative splicing, and recent estimates suggest there are >82 000 transcriptional initiation sites and 128 000 alternative polyadenylation sites for $21 000 human protein coding genes [5]. As the use of many splice sites and alternative promoters or polyadenylation sites is regulated in response to extracellular cues or during development, alternative mRNA isoforms can determine the functions of a gene in different circumstances
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