Autophagy regulation by RNA alternative splicing and implications in human diseases.
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ABSTRACT:
SUBMITTER: Gonzalez-Rodriguez P
PROVIDER: S-EPMC9117662 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
Publications
Autophagy regulation by RNA alternative splicing and implications in human diseases.
González-Rodríguez Patricia P Klionsky Daniel J DJ Joseph Bertrand B
Nature communications 20220518 1
Autophagy and RNA alternative splicing are two evolutionarily conserved processes involved in overlapping physiological and pathological processes. However, the extent of functional connection is not well defined. Here, we consider the role for alternative splicing and generation of autophagy-related gene isoforms in the regulation of autophagy in recent work. The impact of changes to the RNA alternative splicing machinery and production of alternative spliced isoforms on autophagy are reviewed ...[more]
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Project description:Alternative splicing (AS), a vital post-transcription process for eukaryote gene expression regulating, can efficiently improve gene utilization and increase the variety of RNA transcripts and proteins. However, AS of non-coding RNAs (ncRNAs) has not been paid enough attention to compared with that of protein-coding RNAs (mRNAs) for a long time. In fact, AS of ncRNAs, especially long noncoding RNAs (lncRNAs), also plays a significant regulatory role in the human disease. Recently, some bifunctional genes transcribed into both mRNA and lncRNA transcripts by AS have been observed. Here, we focus on the AS of lncRNAs and bifunctional genes producing lncRNA transcripts and propose a strategy for the future research of lncRNA AS.
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Project description:ObjectiveMultiple obesity susceptibility loci have been identified by genome-wide association studies, yet the mechanisms by which these loci influence obesity remain unclear. Alternative splicing could contribute to obesity by regulating the transcriptomic and proteomic diversity of genes in these loci.MethodsBased on a database search, 72 of the 136 genes at the 13 obesity loci encoded multiple protein isoforms. Thus, alternative splicing of these genes in adipose tissue samples was analyzed from the Metabolic Syndrome in Men population-based study and from two weight loss intervention studies (surgical and very low calorie diet).ResultsAlternative splicing was confirmed in 11 genes with PCR capillary electrophoresis in human subcutaneous adipose tissue. Interestingly, differential splicing of TRA2B, BAG6, and MSH5 was observed between lean individuals with normoglycemia and overweight individuals with type 2 diabetes. Of these genes, we detected fat depot-dependent splicing of TRA2B and BAG6 and weight loss-induced regulation of MSH5 splicing in the intervention studies. Finally, body mass index was a major determinant of TRA2B, BAG6, and MSH5 splicing in the combined data.ConclusionsThis study provides evidence for alternative splicing in obesity loci, suggesting that alternative splicing at least in part mediates the obesity-associated risk in these loci.
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Project description:BACKGROUND: Alternative splicing (AS) is a primary mechanism of functional regulation in the human genome, with 60% to 80% of human genes being alternatively spliced. As part of the bovine genome annotation team, we have analysed 4567 bovine AS genes, compared to 16715 human and 16491 mouse AS genes, along with Gene Ontology (GO) analysis. We also analysed the two most important events, cassette exons and intron retention in 94 human disease genes and mapped them to the bovine orthologous genes. Of the 94 human inherited disease genes, a protein domain analysis was carried out for the transcript sequences of 12 human genes that have orthologous genes and have been characterised in cow. RESULTS: Of the 21,755 bovine genes, 4,567 genes (21%) are alternatively spliced, compared to 16,715 (68%) in human and 16,491 (57%) in mouse. Gene-level analysis of the orthologous set suggested that bovine genes show fewer AS events compared to human and mouse genes. A detailed examination of cassette exons across human and cow for 94 human disease genes, suggested that a majority of cassette exons in human were present and constitutive in bovine as opposed to intron retention which exhibited 50% of the exons as present and 50% as absent in cow. We observed that AS plays a major role in disease implications in human through manipulations of essential/functional protein domains. It was also evident that majority of these 12 genes had conservation of all essential domains in their bovine orthologous counterpart, for these human diseases. CONCLUSION: While alternative splicing has the potential to create many mRNA isoforms from a single gene, in cow the majority of genes generate two to three isoforms, compared to six in human and four in mouse. Our analyses demonstrated that a smaller number of bovine genes show greater transcript diversity. GO definitions for bovine AS genes provided 38% more functional information than currently available in the sequence database. Our protein domain analysis helped us verify the suitability of using bovine as a model for human diseases and also recognize the contribution of AS towards the disease phenotypes.
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Project description:The membrane mucin MUC1 is aberrantly expressed in a variety of cancers, and in stomach, it is a ligand for Helicobacter pylori where it plays a role in gastric carcinogenesis. Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5' end of exon 2, but is also reported to be cancer-associated. However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms ofMUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated. Here we show that in both foetal and adult tissues of known genotype, there is clear evidence for the role of rs4072037 in controlling alternative splicing of the 5' exon 2 region of both full-length transcripts and those lacking the TR domain. Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms. In conclusion, over-representation of certain transcripts in tumour material cannot be evaluated without information on the SNP genotype as well.
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Project description:BackgroundAlternatively spliced exons play an important role in the diversification of gene function in most metazoans and are highly regulated by conserved motifs in exons and introns. Two contradicting properties have been associated to evolutionary conserved alternative exons: higher sequence conservation and higher rate of non-synonymous substitutions, relative to constitutive exons. In order to clarify this issue, we have performed an analysis of the evolution of alternative and constitutive exons, using a large set of protein coding exons conserved between human and mouse and taking into account the conservation of the transcript exonic structure. Further, we have also defined a measure of the variation of the arrangement of exonic splicing enhancers (ESE-conservation score) to study the evolution of splicing regulatory sequences. We have used this measure to correlate the changes in the arrangement of ESEs with the divergence of exon and intron sequences.ResultsWe find evidence for a relation between the lack of conservation of the exonic structure and the weakening of the sequence evolutionary constraints in alternative and constitutive exons. Exons in transcripts with non-conserved exonic structures have higher synonymous (dS) and non-synonymous (dN) substitution rates than exons in conserved structures. Moreover, alternative exons in transcripts with non-conserved exonic structure are the least constrained in sequence evolution, and at high EST-inclusion levels they are found to be very similar to constitutive exons, whereas alternative exons in transcripts with conserved exonic structure have a dS significantly lower than average at all EST-inclusion levels. We also find higher conservation in the arrangement of ESEs in constitutive exons compared to alternative ones. Additionally, the sequence conservation at flanking introns remains constant for constitutive exons at all ESE-conservation values, but increases for alternative exons at high ESE-conservation values.ConclusionWe conclude that most of the differences in dN observed between alternative and constitutive exons can be explained by the conservation of the transcript exonic structure. Low dS values are more characteristic of alternative exons with conserved exonic structure, but not of those with non-conserved exonic structure. Additionally, constitutive exons are characterized by a higher conservation in the arrangement of ESEs, and alternative exons with an ESE-conservation similar to that of constitutive exons are characterized by a conservation of the flanking intron sequences higher than average, indicating the presence of more intronic regulatory signals.
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