Prevalent intron retention fine‐tunes gene expression and contributes to cellular senescence

Abstract

Intron retention (IR) is the least well‐understood alternative splicing type in animals, and its prevalence and function in physiological and pathological processes have long been underestimated. Cellular senescence contributes to individual aging and age‐related diseases and can also serve as an important cancer prevention mechanism. Dynamic IR events have been observed in senescence models and aged tissues; however, whether and how IR impacts senescence remain unclear. Through analyzing polyA+ RNA‐seq data from human replicative senescence models, we found IR was prevalent and dynamically regulated during senescence and IR changes negatively correlated with expression alteration of corresponding genes. We discovered that knocking down (KD) splicing factor U2AF1, which showed higher binding density to retained introns and decreased expression during senescence, led to senescence‐associated phenotypes and global IR changes. Intriguingly, U2AF1‐KD‐induced IR changes also negatively correlated with gene expression. Furthermore, we demonstrated that U2AF1‐mediated IR of specific gene (CPNE1 as an example) contributed to cellular senescence. Decreased expression of U2AF1, higher IR of CPNE1, and reduced expression of CPNE1 were also discovered in dermal fibroblasts with age. We discovered prevalent IR could fine‐tune gene expression and contribute to senescence‐associated phenotypes, largely extending the biological significance of IR.

Comprehensive characterization of somatic variants associated with intronic polyadenylation in human cancers

“…For identified SNVs associated with abnormal splicing, we examined whether corresponding intron was retained. IR events were determined using our established intron retention index (IRI) algorithm, which defines IRI as the ratio of read density of the intronic region (RDintron) and the mean read density of flanking upstream exon (RDupexon) and flanking downstream exon (RDdownexon) ( 26 , 27 ). \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$$\begin{equation*}{\rm{IRI}}\,{\rm{ = }}\,\frac{{{\rm{RDintron}}}}{{\left( {{\rm{RDupexon}} + {\rm{RDdownexon}}} \right)/2}}\end{equation*}$$\end{document} …”

Splicing alterations in healthy aging and disease

“…Furthermore, several transcripts with age‐related intron retention events detected in mouse and flies (Adusumalli et al, 2019; Lister et al, 2013; Stilling et al, 2014) were also conserved in the aging human brain (Adusumalli et al, 2019; Mazin et al, 2013). Moreover, an analysis of a dermal fibroblast dataset from young and old people highlighted intron retention as a significant age‐related splicing event (Yao et al, 2020). However, additional studies argue that this is not the only significant trend in age‐related AS; for example, in aging skeletal muscle, skipped exons were the most frequently detected AS event type, many of which were in genes implicated in mitochondrial processes and inflammation (Ubaida‐Mohien et al, 2019).…”

“…Similarly, senescent neuroblastoma cells were shown to suppress expression of SRSF7 (Kadota et al, 2020). Moreover, a recent study uncovered that, in vitro, decreased expression of U2AF1 levels during replicative senescence triggers intron retention in hundreds of transcripts, which in turn downregulates their gene expression (Yao et al, 2020). Interestingly, knockdown of one of the U2AF1 target genes, CNPE1 , impacts senescence associated phenotypes, thus suggesting intron retention might directly contribute to senescence (Yao et al, 2020).…”

“…Moreover, a recent study uncovered that, in vitro, decreased expression of U2AF1 levels during replicative senescence triggers intron retention in hundreds of transcripts, which in turn downregulates their gene expression (Yao et al, 2020). Interestingly, knockdown of one of the U2AF1 target genes, CNPE1 , impacts senescence associated phenotypes, thus suggesting intron retention might directly contribute to senescence (Yao et al, 2020). Finally, several SFs, including PTBP1, have been shown to play a role in SASP production, for example by regulating AS of genes involved in intracellular trafficking, such as EXOC7 (Georgilis et al, 2018).…”

A Deep Exon Cryptic Splice Site Promotes Aberrant Intron Retention in a Von Willebrand Disease Patient

“…Intron retention (IR) is a major form of alternative splicing that regulates expression of many genes during normal differentiation [15][16][17], cellular aging [18], and cellular response to physiological signals [19][20][21]. Aberrant IR, on the other hand, contributes to dysfunctional gene expression in many cancers [22,23] and in other diseases [24][25][26][27][28][29][30].…”