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Dynamic 3'UTR changes during naïve CD4+ T cell activation and proliferation are reverted in the effector/memory state [Iso-Seq]

ABSTRACT: 3’ untranslated regions (3’UTRs) are critical elements of most messenger RNAs: they contain binding sites for RNA-binding proteins (RBP) and microRNAs that affect various aspects of the RNA life cycle including transcript stability. In response to T cell receptor activation, T cells undergo massive expansion during the effector phase of the immune response and dynamically modify their 3’UTRs. Whether this serves to directly regulate the abundance of specific mRNAs or is a secondary effect of proliferation remains unclear. To study 3’UTR dynamics in T helper cells we investigated division-dependent alternative polyadenylation (APA). We generated 3’ end UTR sequencing in naïve, 48h activated (anti-CD3/CD28 cultured), memory and regulatory CD4+ Tcells. 48h activated Tcells were CTV-separated into three populations: cells not yet divided, divided once and twice. 3’UTR length changes were estimated using non-negative matrix factorization approach and partially compared with long-read PacBio sequencing. We found that, in T helper cells, APA events were transient and reverted after effector phase expansion. Using an orthogonal bulk RNAseq dataset, we found that APA genes were not significantly associated with either post-transcriptional or transcriptional regulation, differential gene expression or transcript usage, demonstrating a marginal effect of APA on transcript abundance. 3’UTR sequence analysis revealed conserved binding sites for important microRNAs and RBPs co-evolving with APA events. These results highlight the important role of polyA site usage in the control of cell fate decisions and homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE209603 | GEO | 2023/11/06

REPOSITORIES: GEO

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Dynamic 3'UTR changes during naïve CD4+ T cell activation and proliferation are reverted in the effector/memory state [A-Seq]

Project description:3’ untranslated regions (3’UTRs) are critical elements of most messenger RNA species and can contain binding sites for RNA-binding proteins (RBP) and microRNAs that affect various aspects of RNA life cycles including transcript stability. Cells of the adaptive immune system undergo massive expansion during the effector phase of the immune response and dynamically modify their 3’UTRs in a response to T cell receptor activation. Whether this phenomenon is a secondary effect of proliferation or a mechanism to directly regulate the abundance of specific mRNAs remains unclear. To study 3’UTR dynamics in T helper cells we investigated division-dependent alternative polyadenylation and observed a transient character of global 3’UTR shortening/lengthening in T helper cells that return to a naïve-like polyadenylation state after effector phase expansion. We also showed that 3’UTR lengthening is associated with higher transcript abundance and post-transcriptional regulation than 3’UTR shortening. Sequence analysis of conserved microRNA and RBP binding sites located within varying 3’ UTR regions highlighted the putative involvement of several microRNAs during this process. Our study emphasizes the value of polyadenylation isoforms analysis for understanding cell behaviors, revealing new aspects of the highly complex interplay of transcriptional and post-transcriptional layers in triggering transcript abundance.

2023-11-06 | GSE183424 | GEO

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

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

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 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.

2016-01-11 | GSE73973 | GEO

Alternative polyadenylation alters protein dosage by switching between intronic and 3' UTR sites

Project description:Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' UTR, introns, or exons. Most studies focus on APA within the 3' UTR, but here we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3' UTR APA and are upregulated. This suggests that, in healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.

2022-11-21 | MSV000090759 | MassIVE

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

SRSF7 and SRSF3 affectSRSF7 and SRSF3 affect 3’UTR length in opposite directions by controlling proximal poly(A)-site usage and CFIm levels 3’UTR length in opposite directions by controlling proximal poly(A)-site usage and CFIm levels

Project description:Alternative polyadenylation (APA) refers to the regulated selection of polyadenylation sites (PASs) in transcripts, which affects the length of their 3’ untranslated regions (3’UTRs). APA regulates stage- and tissue-specific gene expression by affecting the stability, subcellular localization or translation rate of transcripts. We have recently shown that SRSF3 and SRSF7, two closely related SR proteins, link APA to mRNA export. However, the underlying mechanism for APA regulation by SRSF3 and SRSF7 remained unknown. Here, we combined iCLIP and 3’-end sequencing to find that both proteins bind upstream of proximal PAS (pPAS), but exert opposing effects on 3’UTR length. We show that SRSF7 enhances pPAS usage in a splicing-independent and concentration-dependent manner by recruiting the cleavage factor FIP1, thereby generating short 3’UTRs. SRSF7-specific domains that are absent in SRSF3 are necessary and sufficient for FIP1 recruitment. SRSF3 promotes long 3’UTRs by maintaining high levels of the cleavage factor Im (CFIm) via alternative splicing. Using iCLIP, we show that CFIm binds before and after the pPASs of SRSF3 targets, which masks them and inhibits polyadenylation. In the absence of SRSF3, CFIm levels are strongly reduced, which exposes the pPASs and leads to shorter 3’UTRs. Conversely, during cellular differentiation, 3’UTRs are massively extended, while the levels of SRSF7 and FIP1 strongly decline. Altogether, our data suggest that SRSF7 acts as a sequence-specific enhancer of pPASs, while SRSF3 inhibits pPAS usage by controlling CFIm levels. Our data shed light on a long-standing puzzle of how one factor (CFIm) can inhibit and enhance PAS usage.

2021-09-09 | PXD018090 | Pride

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

The landscape of alternative polyadenylation during EMT and its regulation by the RNA-binding protein Quaking [PANQKI_HITS-CLIP]

Project description:Epithelial-mesenchymal transition (EMT) plays important roles in tumour progression and is orchestrated by dynamic changes in gene expression. While it is well established that post-transcriptional regulation plays a significant role in EMT, the extent of alternative polyadenylation (APA) during EMT has not yet been explored. Using 3’ end anchored RNA sequencing, we mapped the alternative polyadenylation landscape (APA) following TGF-β-mediated induction of EMT in human mammary epithelial cells and found APA generally causes 3’UTR lengthening during this cell state transition. Investigation of potential mediators of APA indicated the RNA-binding protein Quaking (QKI), a splicing factor induced during EMT, regulates a small subset of events including the length of its own transcript. Analysis of QKI CLIP-seq data identified the binding of QKI within 3’UTRs was enriched near cleavage and polyadenylation sites. Following QKI knockdown, APA of many transcripts are altered to produce predominantly shorter 3’UTRs associated with reduced gene expression. These findings reveal the changes in APA that occur during EMT and identify a potential role for QKI in this process.

2023-12-21 | GSE228928 | GEO

The landscape of alternative polyadenylation during EMT and its regulation by the RNA-binding protein Quaking [PAT-seq]

2023-12-21 | GSE228929 | GEO

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