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Alternative cleavage and polyadenylation in spermatogenesis coordinates chromatin regulation and 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’UTRs in testes. Here we show widespread shortening of 3’UTR by APA during the first wave of spermatogenesis in mouse, with 3’UTRs being the shortest in spermatids. Shortening of 3’UTR eliminates destabilizing elements, such as U-rich elements and transposable elements, which appear to be highly potent for transcript elimination during spermatogenesis. We additionally found widespread regulation of APA in introns and global activation of upstream antisense transcripts during spermatogenesis. Interestingly, genes that display 3’UTR shortening tend to have higher levels of H3K4me3, consistent with the open chromatin feature previously observed in spermatids. Since genes with 3’UTR shortening tend to have functions important for further sperm development after spermatids, when transcription is halted, this result indicates that expression of short, stable mRNAs may serve the purpose of mRNA storage for later translation. Thus, APA in spermatogenesis connects regulation of chromatin status with post-transcriptional control, and impacts sperm maturation.

ORGANISM(S): Mus musculus

PROVIDER: GSE73973 | GEO | 2016/01/11

SECONDARY ACCESSION(S): PRJNA298627

REPOSITORIES: GEO

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Alternative cleavage and polyadenylation in spermatogenesis coordinates chromatin regulation and post-transcriptional control

Project description:Most mammalian genes display alternative cleavage and polyadenylation (APA). Previous studies have indicated preferential expression of APA isoforms with short 3âUTRs in testes. Here we show widespread shortening of 3âUTR by APA during the first wave of spermatogenesis in mouse, with 3âUTRs being the shortest in spermatids. Shortening of 3âUTR eliminates destabilizing elements, such as U-rich elements and transposable elements, which appear to be highly potent for transcript elimination during spermatogenesis. We additionally found widespread regulation of APA in introns and global activation of upstream antisense transcripts during spermatogenesis. Interestingly, genes that display 3âUTR shortening tend to have higher levels of H3K4me3, consistent with the open chromatin feature previously observed in spermatids. Since genes with 3âUTR shortening tend to have functions important for further sperm development after spermatids, when transcription is halted, this result indicates that expression of short, stable mRNAs may serve the purpose of mRNA storage for later translation. Thus, APA in spermatogenesis connects regulation of chromatin status with post-transcriptional control, and impacts sperm maturation. 3'READS of 1 week to 6 week of testis development

2016-01-11 | E-GEOD-73973 | biostudies-arrayexpress

Differentiation of syncytialized trophoblasts elicits widespread 3’UTR shortening that accompanies increased cellular function in protein secretion

Project description:Most eukaryotic genes express alternative polyadenylation (APA) isoforms with different 3’UTR sizes. The APA profile varies across tissue types and under different growth and differentiation conditions. Here we report that, unlike many other cell differentiation lineages, differentiation of syncytiotrophoblasts (SCTs) elicits widespread 3’UTR shortening, as shown in multiple in vitro trophoblast differentiation models as well as in single placental cells at different stages of pregnancy. We show that the 3’UTR shortening is unrelated to cell proliferation, a feature previously associated with 3’UTR size control, but rather accompanies increased cell function in protein secretion. In addition, 3’UTR shortening correlates with increased transcript abundance and is coupled with enhanced intronic APA site usage, suggesting activation of 3’ end processing in SCT differentiation. Together, our data indicate that SCTs utilize APA to express transcripts with short 3’UTRs, which may enhance hormone production and secretion, contributing to their functions in pregnancy.

2020-05-15 | GSE138759 | GEO

Cellular stress alters 3’UTR landscape through alternative polyadenylation and isoform-specific degradation

Project description:Most eukaryotic genes express alternative polyadenylation (APA) isoforms with different lengths of 3’ untranslated region (3’UTR). Here we show arsenic stress elicits global shortening of 3’UTRs through two mechanisms. First, stress leads to immediate shortening of 3’UTR due to preferential usage of proximal cleavage and polyadenylation sites (PASs), as revealed by 3’ end sequencing of newly made RNAs that are metabolically labeled with 4-thiouridine. Second, long 3’UTR isoforms are more rapidly degraded during recovery from stress as compared to short 3’UTR isoforms, further shortening 3’UTR lengths in the cell. Using ribonucleoprotein immunoprecipitation coupled with 3’ end sequencing (3’READS+RIP), we show that the RNA-binding protein T cell-restricted intracellular antigen-1 (Tia1) preferentially interacts with long 3’UTR isoforms via U-rich elements in alternative 3’UTR sequences, and the interaction correlates with stress granule (SG) association during stress and with mRNA decay during recovery from stress, indicating SG-mediated RNA clearance mechanism post stress. Importantly, genes whose 3’UTRs are shortened by APA during stress can evade stress-induced 3’UTR size-based mRNA degradation, leading to higher transcript abundance post stress. Moreover, proliferating and differentiated cells display different extents of 3’UTR shortening after stress, indicating cell type-specific of impact of stress on the 3’UTR landscape. Together, our data indicate that 3’UTR length plays important roles in gene expression in stressed cells, and APA functions as an adaptive stress response mechanism to preserve mRNAs.

2018-06-13 | GSE101851 | GEO

Transcript shortening through alternative polyadenylation promotes gene expression during fracture healing

Project description:Maturation of the 3¢ end of almost all eukaryotic messenger RNAs (mRNAs) requires cleavage and polyadenylation. Most mammalian mRNAs are polyadenylated at different sites within the last exon, generating alternative polyadenylation (APA) isoforms that have the same coding region but distinct 3¢ untranslated regions (UTRs). The 3¢UTR contains motifs that regulate mRNA metabolism; thus, changing the 3¢UTR length via APA can significantly impact gene expression. Endochondral ossification is a central process in bone healing, and the impact of APA on gene expression during this process is unknown. Here, we report widespread utilization of APA that impacts multiple pathways with established roles in bone healing. Importantly, progression of endochondral ossification is typified by global 3¢UTR shortening that is coupled with an increased abundance of shortened transcripts as compared to all other transcripts, underscoring the role of APA in promoting gene expression during endochondral bone formation. Our mechanistic studies of genes that undergo APA in the fracture callus uncover an intricate regulatory network in which APA boosts the expression of collagen, type I, alpha 1 (Col1a1) and Col1a2 genes, which encode the 2 subunits of the abundantly expressed protein collagen 1. APA does so via shortening the 3¢UTRs of Col1a1 and Col1a2 mRNAs, which removes the binding sites of miR-29a-3p that otherwise potently triggered the degradation of both transcripts. Taken together, our study takes the lead in characterizing crucial roles of APA in tailoring the 3¢UTR landscape and regulating gene expression during fracture healing.

2023-01-11 | GSE205053 | GEO

Regulation of alternative polyadenylation by the C2H2-zinc finger protein Sp1 [RNA-Seq]

Project description:About 70% of human genes carry multiple polyadenylation signals, and mRNA 3’end formation is dynamically regulated under different physiological conditions. Global 3’end shortening through alternative polyadenylation (APA) correlates with enhanced cellular proliferation, and 3’ untranslated region (UTR) shortening is a widespread phenomenon in tumour cells, where it appears to enhance tumorigenic properties. However, the mechanisms responsible for this dynamic APA regulation remain incompletely understood. Here we show that transcription factor Sp1 binds directly to RNA in vivo and is a common repressor of distal poly (A) site usage. RNA-sequencing (RNA-seq) analysis identified 2344 genes (36% of total mapped mRNA transcripts) with lengthened 3’UTRs upon Sp1 depletion. Sp1 preferentially binds in vivo within the 3’UTRs of many of these lengthened transcripts and inhibits cleavage at distal sites by interacting physically with subunits of the core cleavage and polyadenylation (CPA) machinery. The 3’UTR lengths of Sp1 target genes in breast cancer patient RNA-seq data correlate with Sp1 expression levels, implicating Sp1-mediated APA regulation in modulating tumorigenic properties. Taken together, our findings reveal an important mechanism for dynamic APA regulation by unraveling a novel function of Sp1.

2022-01-28 | GSE165771 | GEO

Regulation of alternative polyadenylation by the C2H2-zinc finger protein Sp1 [ChIP-Seq]

2022-01-28 | GSE165683 | GEO

Regulation of alternative polyadenylation by the C2H2-zinc finger protein Sp1 [CLIP-seq]

2022-01-28 | GSE165739 | GEO

U1 snRNP regulates alternative polyadenylation in DNA damage response

Project description:The DNA damage response (DDR) involves coordinated control of gene expression and DNA repair. Using deep sequencing we found widespread changes of alternative cleavage and polyadenylation (APA) site usage upon UV-treatment in mammalian cells. APA regulation in the 3’ untranslated region (3’UTR) is substantial, leading to both shortening and lengthening of 3’UTRs. Interestingly, a strong activation of intronic APA sites is detected, resulting in widespread expression of truncated transcripts. Intronic APA events are biased to the 5’ end of genes and affect gene groups with important functions in DDR. Moreover, intronic APA site activation during DDR correlates with a decrease in U1 snRNA levels, and this is reversed by U1 snRNA overexpression. Importantly, U1 snRNA overexpression decreases UV-induced apoptosis. Together, these studies describe a significant gene regulatory scheme in DDR where U1 snRNP impacts gene expression via APA.

2016-05-01 | GSE71801 | GEO

Activation and inhibition of nonsense-mediated mRNA decay control the abundance of alternative polyadenylation products

Project description:Alternative polyadenylation (APA) produces transcript 3’ untranslated regions (3’UTRs) with distinct sequences, lengths, stability, and functions. We show here that APA products include a class of cryptic nonsense-mediated mRNA decay (NMD) substrates with extended 3’UTRs that gene- or transcript-level analyses of NMD often fail to detect. Transcriptome-wide, the core NMD factor UPF1 preferentially recognizes long 3’UTR products of APA, leading to their systematic downregulation. Further, we find that many APA events consistently observed in multiple tumor types are controlled by NMD. Additionally, PTBP1, previously implicated in direct modulation of co-transcriptional polyA site choice, regulates the balance of short and long 3’UTR isoforms by inhibiting NMD. Our data suggest that PTBP1 binding near polyA sites can drive production of long 3’UTR APA products in the nucleus and/or protect them from decay in the cytoplasm. Together, our findings reveal a widespread role for NMD in shaping the outcomes of APA.

2020-05-28 | GSE138736 | GEO

m6A level and isoform characterization sequencing (m6A-LAIC-seq) reveal the census and complexity of the m6A epitranscriptome

Project description:N6-methyladenosine (m6A) is a widespread reversible chemical modification of RNAs, implicated in many aspects of RNA metabolism. Little quantitative information exists as to either how many transcript copies of particular genes are m6A modified (âm6A levelsâ), or the relationship of m6A modification(s) to alternative RNA isoforms. To deconvolute the m6A epitranscriptome, we developed m6A level and isoform-characterization sequencing (m6A-LAIC-seq). We found that cells exhibit a broad range of non-stoichiometric m6A levels with cell type specificity. At the level of isoform characterization, we discovered widespread differences in use of tandem alternative polyadenylation (APA) sites by methylated and nonmethylated transcript isoforms of individual genes. Strikingly, there is a strong bias for methylated transcripts to be coupled with proximal APA sites, resulting in shortened 3â untranslated regions (3â-UTRs), while nonmethylated transcript isoforms tend to use distal APA sites. m6A-LAIC-seq yields a new perspective on transcriptome complexity and links APA usage to m6A modifications. m6A-LAIC-seq of H1-ESC and GM12878 cell lines, each cell line has two replicates

2016-06-24 | E-GEOD-66086 | biostudies-arrayexpress

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