Alternative Polyadenylation: a new frontier in post transcriptional regulation

Ren, Fanggang; Zhang, Na; Zhang, Lan; Miller, Eugene H.; Pu, Jeffrey J.

doi:10.1186/s40364-020-00249-6

Cited by 57 publications

(40 citation statements)

References 101 publications

(147 reference statements)

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“…In conclusion, our findings from 1221 current and former smokers demonstrate widespread effects of smoking on alternative isoform regulation, highlighting specifically posttranscriptional mechanisms of APA and 3′ UTR lengthening. In the future, when longitudinal follow-up data are available for these subjects, we may be able to relate these posttranscriptional events to prospective health outcomes, and develop APA biomarkers and therapeutic targets for smoking-related diseases [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoking-associated isoform switching and 3′ UTR lengthening via alternative polyadenylation

et al. 2021

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Cigarette smoking induces a profound transcriptomic and systemic inflammatory response. Previous studies have focused on gene level differential expression of smoking, but the genome-wide effects of smoking on alternative isoform regulation have not yet been described. We conducted RNA sequencing in whole-blood samples of 454 current and 767 former smokers in the COPDGene Study, and we analyzed the effects of smoking on differential usage of isoforms and exons. At 10% FDR, we detected 3167 differentially expressed genes, 945 differentially used isoforms and 160 differentially used exons. Isoform switch analysis revealed widespread 3′ UTR lengthening associated with cigarette smoking. The lengthening of these 3′ UTRs was consistent with alternative usage of distal polyadenylation sites, and these extended 3′ UTR regions were significantly enriched with functional sequence elements including microRNA and RNA-protein binding sites. These findings warrant further studies on alternative polyadenylation events as potential biomarkers and novel therapeutic targets for smoking-related diseases.

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Section: Discussionmentioning

confidence: 99%

Cigarette smoking-associated isoform switching and 3′ UTR lengthening via alternative polyadenylation

et al. 2021

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“…In conclusion, our findings from 1,221 current and former smokers demonstrate widespread effects of smoking on alternative isoform regulation, highlighting specifically posttranscriptional mechanisms of APA and 3' UTR lengthening. In the future, when longitudinal follow-up data are available for these subjects, we may be able to relate these posttranscriptional events to prospective health outcomes, and develop APA biomarkers and therapeutic targets for smoking-related diseases 66 .…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoking-Associated Isoform Switching and 3’ UTR Lengthening Via Alternative Polyadenylation

Platig

Lee

Boueiz

et al. 2021

Preprint

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Cigarette smoking accounts for approximately one in five deaths in the United States. Previous genomic studies have primarily focused on gene level differential expression to identify related molecular signatures and pathways, but the genome-wide effects of smoking on alternative isoform regulation and posttranscriptional modulation have not yet been described. We conducted RNA sequencing (RNA-seq) in whole-blood samples of 454 current and 767 former smokers in COPDGene Study. We assessed the association of current smoking with differential expression of genes and isoforms and differential usage of isoforms and exons. At 10% FDR, we detected 3,167 differentially expressed genes, 2,014 differentially expressed isoforms, 945 differentially used isoforms and 160 differentially used exons. Genes containing differentially used isoforms were enriched in biological pathways involving GTPase activity and innate immunity. The majority of these genes were not differentially expressed, thus not identifiable from conventional differential gene expression analysis. Isoform switch analysis revealed for the first time widespread 3-prime UTR lengthening associated with cigarette smoking, where current smokers were found to have higher expression and usage of isoforms with markedly longer 3-prime UTRs. The lengthening of 3-prime UTRs appears to be mediated through alternative usage of distal polyadenylation sites, and these extended 3-prime UTR regions are significantly enriched with functional sequence elements including adenylate-uridylate (AU)-rich elements, microRNA and RNA-protein binding sites. Expression quantitative trait locus analyses on differentially used 3-prime UTRs identified 79 known GWAS variants associated with multiple smoking-related human diseases and traits. Smoking elicits widespread transcriptional and posttranscriptional alterations with disease implications. It induces alternative polyadenylation (APA) events resulting in a switch towards the usage of isoforms with strikingly longer 3-prime UTRs in genes related to multiple biological pathways including GTPase activity and innate immunity. The extended 3-prime UTR regions are enriched with functional sequence elements facilitating post-transcriptional regulation of protein expression and mRNA stability. These findings warrant further studies on APA events as potential biomarkers and novel therapeutic targets for smoking-related diseases.

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“…APA expands cellular transcriptomic diversity by generating distinct mRNA isoforms [21]. Depending on the location of polyadenylation sites (PASs), APA can be classified into two types: UTR-APA and coding region-APA (CR-APA) [22]. The presence of APA sites in 3 -UTRs of mRNAs generates transcript isoforms with the same coding region but with different lengths of 3 -UTR regions, thus giving rise to distinct interactions of mRNA isoforms with RNAbinding proteins and non-coding RNAs like microRNA and lncRNAs [21].…”

Section: Mrna Alternative Polyadenylationmentioning

confidence: 99%

RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis

Chatterjee

Shen

Majumder

2021

IJMS

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The intrinsic cellular heterogeneity and molecular complexity of the mammalian nervous system relies substantially on the dynamic nature and spatiotemporal patterning of gene expression. These features of gene expression are achieved in part through mechanisms involving various epigenetic processes such as DNA methylation, post-translational histone modifications, and non-coding RNA activity, amongst others. In concert, another regulatory layer by which RNA bases and sugar residues are chemically modified enhances neuronal transcriptome complexity. Similar RNA modifications in other systems collectively constitute the cellular epitranscriptome that integrates and impacts various physiological processes. The epitranscriptome is dynamic and is reshaped constantly to regulate vital processes such as development, differentiation and stress responses. Perturbations of the epitranscriptome can lead to various pathogenic conditions, including cancer, cardiovascular abnormalities and neurological diseases. Recent advances in next-generation sequencing technologies have enabled us to identify and locate modified bases/sugars on different RNA species. These RNA modifications modulate the stability, transport and, most importantly, translation of RNA. In this review, we discuss the formation and functions of some frequently observed RNA modifications—including methylations of adenine and cytosine bases, and isomerization of uridine to pseudouridine—at various layers of RNA metabolism, together with their contributions to abnormal physiological conditions that can lead to various neurodevelopmental and neurological disorders.

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Alternative Polyadenylation: a new frontier in post transcriptional regulation

Cited by 57 publications

References 101 publications

Cigarette smoking-associated isoform switching and 3′ UTR lengthening via alternative polyadenylation

Cigarette smoking-associated isoform switching and 3′ UTR lengthening via alternative polyadenylation

Cigarette Smoking-Associated Isoform Switching and 3’ UTR Lengthening Via Alternative Polyadenylation

RNA Modifications and RNA Metabolism in Neurological Disease Pathogenesis

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