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Shortening of 3' UTRs in most cell types composing tumor tissues implicates alternative polyadenylation in protein metabolism.

ABSTRACT: During pre-mRNA maturation 3' end processing can occur at different polyadenylation sites in the 3' untranslated region (3' UTR) to give rise to transcript isoforms that differ in the length of their 3' UTRs. Longer 3' UTRs contain additional cis-regulatory elements that impact the fate of the transcript and/or of the resulting protein. Extensive alternative polyadenylation (APA) has been observed in cancers, but the mechanisms and roles remain elusive. In particular, it is unclear whether the APA occurs in the malignant cells or in other cell types that infiltrate the tumor. To resolve this, we developed a computational method, called SCUREL, that quantifies changes in 3' UTR length between groups of cells, including cells of the same type originating from tumor and control tissue. We used this method to study APA in human lung adenocarcinoma (LUAD). SCUREL relies solely on annotated 3' UTRs and on control systems such as T cell activation, and spermatogenesis gives qualitatively similar results at much greater sensitivity compared to the previously published scAPA method. In the LUAD samples, we find a general trend toward 3' UTR shortening not only in cancer cells compared to the cell type of origin, but also when comparing other cell types from the tumor vs. the control tissue environment. However, we also find high variability in the individual targets between patients. The findings help in understanding the extent and impact of APA in LUAD, which may support improvements in diagnosis and treatment.

SUBMITTER: Burri D

PROVIDER: S-EPMC8594477 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells.

Project description:In cancer cells, genetic alterations can activate proto-oncogenes, thereby contributing to tumorigenesis. However, the protein products of oncogenes are sometimes overexpressed without alteration of the proto-oncogene. Helping to explain this phenomenon, we found that when compared to similarly proliferating nontransformed cell lines, cancer cell lines often expressed substantial amounts of mRNA isoforms with shorter 3' untranslated regions (UTRs). These shorter isoforms usually resulted from alternative cleavage and polyadenylation (APA). The APA had functional consequences, with the shorter mRNA isoforms exhibiting increased stability and typically producing ten-fold more protein, in part through the loss of microRNA-mediated repression. Moreover, expression of the shorter mRNA isoform of the proto-oncogene IGF2BP1/IMP-1 led to far more oncogenic transformation than did expression of the full-length, annotated mRNA. The high incidence of APA in cancer cells, with consequent loss of 3'UTR repressive elements, suggests a pervasive role for APA in oncogene activation without genetic alteration.

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Biased alternative polyadenylation in human tissues.

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| S-EPMC1414089 | biostudies-literature

Widespread transcript shortening through alternative polyadenylation in secretory cell differentiation.

Project description:Most eukaryotic genes produce alternative polyadenylation (APA) isoforms. Here we report that, unlike previously characterized cell lineages, differentiation of syncytiotrophoblast (SCT), a cell type critical for hormone production and secretion during pregnancy, elicits widespread transcript shortening through APA in 3'UTRs and in introns. This global APA change is observed in multiple in vitro trophoblast differentiation models, and in single cells from placentas at different stages of pregnancy. Strikingly, the transcript shortening is unrelated to cell proliferation, a feature previously associated with APA control, but instead accompanies increased secretory functions. We show that 3'UTR shortening leads to transcripts with higher mRNA stability, which augments transcriptional activation, especially for genes involved in secretion. Moreover, this mechanism, named secretion-coupled APA (SCAP), is also executed in B cell differentiation to plasma cells. Together, our data indicate that SCAP tailors the transcriptome during formation of secretory cells, boosting their protein production and secretion capacity.

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APAatlas: decoding alternative polyadenylation across human tissues.

Project description:Alternative polyadenylation (APA) is an RNA-processing mechanism on the 3' terminus that generates distinct isoforms of mRNAs and/or other RNA polymerase II transcripts with different 3'UTR lengths. Widespread APA affects post-transcriptional gene regulation in mRNA translation, stability, and localization, and exhibits strong tissue specificity. However, no existing database provides comprehensive information about APA events in a large number of human normal tissues. Using the RNA-seq data from the Genotype-Tissue Expression project, we systematically identified APA events from 9475 samples across 53 human tissues and examined their associations with multiple traits and gene expression across tissues. We further developed APAatlas, a user-friendly database (https://hanlab.uth.edu/apa/) for searching, browsing and downloading related information. APAatlas will help the biomedical research community elucidate the functions and mechanisms of APA events in human tissues.

| S-EPMC6943053 | biostudies-literature

Alternative Polyadenylation Modification Patterns Reveal Essential Posttranscription Regulatory Mechanisms of Tumorigenesis in Multiple Tumor Types.

Project description:Among various risk factors for the initiation and progression of cancer, alternative polyadenylation (APA) is a remarkable endogenous contributor that directly triggers the malignant phenotype of cancer cells. APA affects biological processes at a transcriptional level in various ways. As such, APA can be involved in tumorigenesis through gene expression, protein subcellular localization, or transcription splicing pattern. The APA sites and status of different cancer types may have diverse modification patterns and regulatory mechanisms on transcripts. Potential APA sites were screened by applying several machine learning algorithms on a TCGA-APA dataset. First, a powerful feature selection method, minimum redundancy maximum relevancy, was applied on the dataset, resulting in a feature list. Then, the feature list was fed into the incremental feature selection, which incorporated the support vector machine as the classification algorithm, to extract key APA features and build a classifier. The classifier can classify cancer patients into cancer types with perfect performance. The key APA-modified genes had a potential prognosis ability because of their significant power in the survival analysis of TCGA pan-cancer data.

| S-EPMC7315320 | biostudies-literature

Discovery of alternative polyadenylation dynamics from single cell types.

Project description:Alternative polyadenylation (APA) occurs in the process of mRNA maturation by adding a poly(A) tail at different locations, resulting increased diversity of mRNA isoforms and contributing to the complexity of gene regulatory network. Benefit from the development of high-throughput sequencing technologies, we could now delineate APA profiles of transcriptomes at an unprecedented pace. Especially the single cell RNA sequencing (scRNA-seq) technologies provide us opportunities to interrogate biological details of diverse and rare cell types. Despite increasing evidence showing that APA is involved in the cell type-specific regulation and function, efficient and specific laboratory methods for capturing poly(A) sites at single cell resolution are underdeveloped to date. In this review, we summarize existing experimental and computational methods for the identification of APA dynamics from diverse single cell types. A future perspective is also provided.

| S-EPMC7200215 | biostudies-literature

Single-cell alternative polyadenylation analysis delineates GABAergic neuron types.

Project description:BackgroundAlternative polyadenylation (APA) is emerging as an important mechanism in the post-transcriptional regulation of gene expression across eukaryotic species. Recent studies have shown that APA plays key roles in biological processes, such as cell proliferation and differentiation. Single-cell RNA-seq technologies are widely used in gene expression heterogeneity studies; however, systematic studies of APA at the single-cell level are still lacking.ResultsHere, we described a novel computational framework, SAPAS, that utilizes 3'-tag-based scRNA-seq data to identify novel poly(A) sites and quantify APA at the single-cell level. Applying SAPAS to the scRNA-seq data of phenotype characterized GABAergic interneurons, we identified cell type-specific APA events for different GABAergic neuron types. Genes with cell type-specific APA events are enriched for synaptic architecture and communications. In further, we observed a strong enrichment of heritability for several psychiatric disorders and brain traits in altered 3' UTRs and coding sequences of cell type-specific APA events. Finally, by exploring the modalities of APA, we discovered that the bimodal APA pattern of Pak3 could classify chandelier cells into different subpopulations that are from different laminar positions.ConclusionsWe established a method to characterize APA at the single-cell level. When applied to a scRNA-seq dataset of GABAergic interneurons, the single-cell APA analysis not only identified cell type-specific APA events but also revealed that the modality of APA could classify cell subpopulations. Thus, SAPAS will expand our understanding of cellular heterogeneity.

| S-EPMC8299648 | biostudies-literature

scMAPA: Identification of cell-type-specific alternative polyadenylation in complex tissues.

Project description:BackgroundAlternative polyadenylation (APA) causes shortening or lengthening of the 3'-untranslated region (3'-UTR) of genes (APA genes) in diverse cellular processes such as cell proliferation and differentiation. To identify cell-type-specific APA genes in scRNA-Seq data, current bioinformatic methods have several limitations. First, they assume certain read coverage shapes in the scRNA-Seq data, which can be violated in multiple APA genes. Second, their identification is limited between 2 cell types and not directly applicable to the data of multiple cell types. Third, they do not control undesired source of variance, which potentially introduces noise to the cell-type-specific identification of APA genes.FindingsWe developed a combination of a computational change-point algorithm and a statistical model, single-cell Multi-group identification of APA (scMAPA). To avoid the assumptions on the read coverage shape, scMAPA formulates a change-point problem after transforming the 3' biased scRNA-Seq data to represent the full-length 3'-UTR signal. To identify cell-type-specific APA genes while adjusting for undesired source of variation, scMAPA models APA isoforms in consideration of the cell types and the undesired source. In our novel simulation data and data from human peripheral blood mononuclear cells, scMAPA outperforms existing methods in sensitivity, robustness, and stability. In mouse brain data consisting of multiple cell types sampled from multiple regions, scMAPA identifies cell-type-specific APA genes, elucidating novel roles of APA for dividing immune cells and differentiated neuron cells and in multiple brain disorders.ConclusionsscMAPA elucidates the cell-type-specific function of APA events and sheds novel insights into the functional roles of APA events in complex tissues.

| S-EPMC9055853 | biostudies-literature

Transcript shortening through alternative polyadenylation promotes gene expression during fracture healing

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2023-01-11 | GSE205053 | GEO

Exploring mRNA 3'-UTR G-quadruplexes: evidence of roles in both alternative polyadenylation and mRNA shortening.

Project description:Guanine-rich RNA sequences can fold into non-canonical, four stranded helical structures called G-quadruplexes that have been shown to be widely distributed within the mammalian transcriptome, as well as being key regulatory elements in various biological mechanisms. That said, their role within the 3'-untranslated region (UTR) of mRNA remains to be elucidated and appreciated. A bioinformatic analysis of the 3'-UTRs of mRNAs revealed enrichment in G-quadruplexes. To shed light on the role(s) of these structures, those found in the LRP5 and FXR1 genes were characterized both in vitro and in cellulo. The 3'-UTR G-quadruplexes were found to increase the efficiencies of alternative polyadenylation sites, leading to the expression of shorter transcripts and to possess the ability to interfere with the miRNA regulatory network of a specific mRNA. Clearly, G-quadruplexes located in the 3'-UTRs of mRNAs are cis-regulatory elements that have a significant impact on gene expression.

| S-EPMC3675481 | biostudies-literature

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