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Splicing alterations in healthy aging and disease

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Abstract Alternative RNA splicing is a key step in gene expression that allows generation of numerous messenger RNA transcripts encoding proteins of varied functions from the same gene. It is thus a rich source of proteomic and functional diversity. Alterations in alternative RNA splicing are observed both during healthy aging and in a number of human diseases, several of which display premature aging phenotypes or increased incidence with age. Age‐associated splicing alterations include differential splicing of genes associated with hallmarks of aging, as well as changes in the levels of core spliceosomal genes and regulatory splicing factors. Here, we review the current known links between alternative RNA splicing, its regulators, healthy biological aging, and diseases associated with aging or aging‐like phenotypes. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing
The splicing machinery. (a) Graphical representation of the stepwise assembly of spliceosomal complexes on a pre‐mRNA molecule and catalysis of the splicing reaction to generate mature spliced mRNA (5′SS, 5′ splice site; BPS, branch point site; Py‐tract, polypyrimidine tract). (b) In addition to core spliceosomal components, regulatory splicing factors (SFs) acting as positive regulators (e.g., SRSF1 to SRFS12, TRA2α and TRA2β), or negative regulators (e.g., HNRNPA1, HNRNPH3, HNRNPM, HNRNPDL, etc.), can bind to exonic or intronic splicing enhancer (ESE or ISE) or silencer (ESS or ISS) sequences to fine tune splicing and promote exon inclusion or skipping. (c) Alternatively spliced sequences can be classified into the following patterns: cassette exon, alternative 5′ or 3′ splice site usage, inclusion of mutually exclusive exons, intron retention, alternative first or last exons. Alternative first exons arise as a result of both alternative promoter usage and alternative splicing, while alternative last exons arise as a result of both alternative polyA usage and alternative splicing
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Splicing events associated with senescence. Senescence hallmarks include senescence‐associated heterochromatin foci (SAHF), loss of nuclear laminin, increased reactive oxygen species (ROS), expression of senescence associated β‐galactosidase (B‐Gal), and senescence‐associated secretory phenotype (SASP). Changes in splicing in TP53, EXOC7, ING1, or ENG gene have been reported to impact these senescence hallmarks. Schematic structures of AS isoforms, along with known SF regulators are shown. For each p53 isoform, the regions alternatively spliced are highlighted, and the protein domain encoded by each exon is indicated (DB, DNA binding domain; OD, oligomerization domain; TD, transactivation domain)
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Age‐related splicing alterations. Old versus young tissues and cells exhibit alterations in splicing that can be caused by mutations in, or changes in the levels of, splicing regulatory factors, the latter of which can occur due to copy number changes, or alterations in the epigenetic, transcriptional, posttranscriptional, or posttranslational regulation of SFs in response to signaling changes. These changes in SF levels lead to alterations in alternative splicing (AS) of their downstream targets, promoting events that follow one of the following patterns: cassette exon (CA), alternative 5′ or 3′ splice site selection (A5′SS or A3′SS), inclusion of mutually exclusive exons (MXE), or intron retention (IR). Many of the resulting AS isoforms occur in genes involved in cellular pathways associated with aging hallmarks
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Age‐related changes in splicing factor (SF) levels detected across multiple studies. Differential expression of genes or proteins implicated in AS regulation, including spliceosomal components, SR proteins, HNRNP proteins, or other regulatory factors, as measured by micro‐array, RNA‐seq, targeted QPCR, or proteomics, in tissues from young versus old human (h) or mouse (m). Blood samples are (i) human leukocytes (ages ranging from 30‐ to 104‐years old) (Harries et al., 2011); (ii) human peripheral blood (lnCHIANTI study, 30–104‐years old) (Holly et al., 2013); (iii) human peripheral blood (SAFHS study, 15–94‐years old) (Holly et al., 2013); (iv) human peripheral blood (15–105‐years old) (Peters et al., 2015); and (v) human whole blood (PIVUS study, comparing 70‐ vs. 80‐years old) (Balliu et al., 2019). Brain samples are from (i) human pre‐frontal cortex and cerebellum (0–98‐years old) (Mazin et al., 2013); (ii) human whole brain (16–102‐years old) (Tollervey, Curk, et al., 2011); (iii) mouse cortex (postnatal day 7 vs. 21 months) (Weyn‐Vanhentenryck et al., 2018); (iv) mouse cerebral cortex (postnatal day 1 vs. day 56) (Kadota et al., 2020); and (v) mouse hippocampus (2 vs. 24 or 29 months) (Stilling et al., 2014). Liver samples are from (i) human liver (1–85‐years old) (Chaturvedi et al., 2015); and (ii) mouse hepatocytes (postnatal day 1 vs. day 56) (Kadota et al., 2020) respectively. Mouse skin samples (4 vs. 18 or 28 months) are from Rodriguez et al. (2016). Heart samples are from mouse cardiomyocytes (postnatal day 1 vs. day 56) (Kadota et al., 2020). Skeletal muscle samples are from (i) mouse (4 vs. 18 or 28 months) (Rodriguez et al., 2016); and (ii) human (20–29 years vs. 65–71 years) (Welle et al., 2004); (iii) human (21–27 years vs. 67–75 years) (Welle et al., 2003); and (v) human (GESTALT study, 20–87 years) (Ubaida‐Mohien et al., 2019)
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RNA Processing > Splicing Regulation/Alternative Splicing
RNA in Disease and Development > RNA in Disease

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