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Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control.

ABSTRACT: Most mammalian genes display alternative cleavage and polyadenylation (APA). Previous studies have indicated preferential expression of APA isoforms with short 3' untranslated regions (3'UTRs) in testes.By deep sequencing of the 3' end region of poly(A)?+ transcripts, we report widespread shortening of 3'UTR through APA during the first wave of spermatogenesis in mouse, with 3'UTR size being the shortest in spermatids. Using genes without APA as a control, we show that shortening of 3'UTR eliminates destabilizing elements, such as U-rich elements and transposable elements, which appear highly potent during spermatogenesis. We additionally found widespread regulation of APA events in introns and exons that can affect the coding sequence of transcripts and global activation of antisense transcripts upstream of the transcription start site, suggesting modulation of splicing and initiation of transcription during spermatogenesis. Importantly, genes that display significant 3'UTR shortening tend to have functions critical for further sperm maturation, and testis-specific genes display greater 3'UTR shortening than ubiquitously expressed ones, indicating functional relevance of APA to spermatogenesis. Interestingly, genes with shortened 3'UTRs tend to have higher RNA polymerase II and H3K4me3 levels in spermatids as compared to spermatocytes, features previously known to be associated with open chromatin state.Our data suggest that open chromatin may create a favorable cis environment for 3' end processing, leading to global shortening of 3'UTR during spermatogenesis. mRNAs with shortened 3'UTRs are relatively stable thanks to evasion of powerful mRNA degradation mechanisms acting on 3'UTR elements. Stable mRNAs generated in spermatids may be important for protein production at later stages of sperm maturation, when transcription is globally halted.

SUBMITTER: Li W

PROVIDER: S-EPMC4724118 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control.

Li Wencheng W Park Ji Yeon JY Zheng Dinghai D Hoque Mainul M Yehia Ghassan G Tian Bin B

BMC biology 20160122

<h4>Background</h4>Most mammalian genes display alternative cleavage and polyadenylation (APA). Previous studies have indicated preferential expression of APA isoforms with short 3' untranslated regions (3'UTRs) in testes.<h4>Results</h4>By deep sequencing of the 3' end region of poly(A) + transcripts, we report widespread shortening of 3'UTR through APA during the first wave of spermatogenesis in mouse, with 3'UTR size being the shortest in spermatids. Using genes without APA as a control, we s ...[more]

PMID: 26801249

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Project description:BackgroundColorectal cancer (CRC) is one of the leading causes of cancer death worldwide. microRNAs (miRNAs) repress gene expression by binding to complementary sequences in the 3' untranslated region (3'UTR) of target mRNAs. Alternative polyadenylation (APA) are relevant to the variability of the 3'UTR of mRNA. However, the posttranscriptional dysregulation of miRNAs and APA in CRC are poorly understood.MethodIn this study, we conducted small RNA sequencing to identify differentially expressed miRNAs (DERs) and their target genes. Function analysis on DER-target genes can explain the regulation roles of miRNAs in CRC. The mutual regulation of miRNAs and APA was analyzed by combining miRNA data to 3'UTR alteration using 3' termini of polyadenylated RNAs sequencing (3T-seq) technique, and this was validated using TCGA gene expression data.ResultsOur results showed 64 significant differentially expressed miRNAs (DERs) in CRC patients. Their target genes were related to cell adhesion and transcription regulation and were prevailingly involved in the CRC-related pathway. Integrative analysis of the miRNA and APA profile revealed 16 DERs were correlated with 12 polyadenylation factors, and six of them were significantly differently expressed in CRC. We also found four DERs that lost binding sites due to APA and showed a positive correlation between the miRNA and gene expression.ConclusionOur study found that miRNAs regulated APA by modulating key polyadenylation factors, and several miRNAs lost their suppression on mRNA due to APA. Associating this with gene expression may provide some important clues for a deeper study of posttranscriptional cellular regulation and biomarker research in CRC. Our data provided the first evidence that the interaction between miRNAs and APA associated with gene expression could serve as biomarkers for CRC, suggesting that hsa-miR-133a-3p and MLEC, hsa-miR-145-5p and SET, hsa-miR-1-3p and PPIA, and hsa-miR-378d and YY1 might be novel and potential biomarkers in improving the diagnosis of CRC.

Dataset Information

Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control.

Publications

Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control.

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