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Neuron Sep 2021Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity....
Neuronal alternative splicing is a key gene regulatory mechanism in the brain. However, the spliceosome machinery is insufficient to fully specify splicing complexity. In considering the role of the epigenome in activity-dependent alternative splicing, we and others find the histone modification H3K36me3 to be a putative splicing regulator. In this study, we found that mouse cocaine self-administration caused widespread differential alternative splicing, concomitant with the enrichment of H3K36me3 at differentially spliced junctions. Importantly, only targeted epigenetic editing can distinguish between a direct role of H3K36me3 in splicing and an indirect role via regulation of splice factor expression elsewhere on the genome. We targeted Srsf11, which was both alternatively spliced and H3K36me3 enriched in the brain following cocaine self-administration. Epigenetic editing of H3K36me3 at Srsf11 was sufficient to drive its alternative splicing and enhanced cocaine self-administration, establishing the direct causal relevance of H3K36me3 to alternative splicing of Srsf11 and to reward behavior.
Topics: Alternative Splicing; Animals; Behavior, Addictive; Chromatin; Cocaine; Dopamine Uptake Inhibitors; Epigenesis, Genetic; Female; Male; Mice; Mice, Inbred C57BL; Reward; Self Administration
PubMed: 34480866
DOI: 10.1016/j.neuron.2021.08.008 -
Pharmacological Reviews Jan 2017More than 95% of genes in the human genome are alternatively spliced to form multiple transcripts, often encoding proteins with differing or opposing function. The... (Review)
Review
More than 95% of genes in the human genome are alternatively spliced to form multiple transcripts, often encoding proteins with differing or opposing function. The control of alternative splicing is now being elucidated, and with this comes the opportunity to develop modulators of alternative splicing that can control cellular function. A number of approaches have been taken to develop compounds that can experimentally, and sometimes clinically, affect splicing control, resulting in potential novel therapeutics. Here we develop the concepts that targeting alternative splicing can result in relatively specific pathway inhibitors/activators that result in dampening down of physiologic or pathologic processes, from changes in muscle physiology to altering angiogenesis or pain. The targets and pharmacology of some of the current inhibitors/activators of alternative splicing are demonstrated and future directions discussed.
Topics: Alternative Splicing; Animals; Drug Discovery; Gene Expression Regulation; Humans; Molecular Targeted Therapy; RNA; Signal Transduction; Transcription, Genetic
PubMed: 28034912
DOI: 10.1124/pr.115.011239 -
The Journal of Steroid Biochemistry and... Apr 2015The active form of vitamin D (1α,25-dihydroxyvitamin D, 1,25(OH)2D) exerts its genomic effects via binding to a nuclear high-affinity vitamin D receptor (VDR). Recent... (Review)
Review
The active form of vitamin D (1α,25-dihydroxyvitamin D, 1,25(OH)2D) exerts its genomic effects via binding to a nuclear high-affinity vitamin D receptor (VDR). Recent deep sequencing analysis of VDR binding locations across the complete genome has significantly expanded our understanding of the actions of vitamin D and VDR on gene transcription. However, these studies have also promoted appreciation of the extra-transcriptional impact of vitamin D on gene expression. It is now clear that vitamin D interacts with the epigenome via effects on DNA methylation, histone acetylation, and microRNA generation to maintain normal biological functions. There is also increasing evidence that vitamin D can influence pre-mRNA constitutive splicing and alternative splicing, although the mechanism for this remains unclear. Pre-mRNA splicing has long been thought to be a post-transcription RNA processing event, but current data indicate that this occurs co-transcriptionally. Several steroid hormones have been recognized to coordinately control gene transcription and pre-mRNA splicing through the recruitment of nuclear receptor co-regulators that can both control gene transcription and splicing. The current review will discuss this concept with specific reference to vitamin D, and the potential role of heterogeneous nuclear ribonucleoprotein C (hnRNPC), a nuclear factor with an established function in RNA splicing. hnRNPC, has been shown to be involved in the VDR transcriptional complex as a vitamin D-response element-binding protein (VDRE-BP), and may act as a coupling factor linking VDR-directed gene transcription with RNA splicing. In this way hnRNPC may provide an additional mechanism for the fine-tuning of vitamin D-regulated target gene expression. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
Topics: Alternative Splicing; Gene Expression Regulation; Humans; RNA; Receptors, Calcitriol; Vitamin D; Vitamins
PubMed: 25447737
DOI: 10.1016/j.jsbmb.2014.09.025 -
Current Opinion in Neurobiology Aug 2019Dynamic changes in alternative splicing during the life cycle of neurons support development and plasticity, and are implicated in disease pathology. Cell-specific... (Review)
Review
Dynamic changes in alternative splicing during the life cycle of neurons support development and plasticity, and are implicated in disease pathology. Cell-specific alternative splicing programs coordinate exon selection across networks of functionally connected genes. In this opinion piece, we highlight recent publications that identify some of the molecular mechanisms-RNA and DNA binding proteins and epigenetic modifications-which direct cell-specific exon selection during pre-mRNA splicing. Aberrant splicing patterns are signature features of a growing number of diseases of the nervous system. Recent publications demonstrate the value of delineating basic mechanisms that dictate exon choice to inform the development of new therapeutic strategies that correct or compensate for damaging deficits in alternative splicing.
Topics: Alternative Splicing; Exons; Neurons; RNA Splicing
PubMed: 30703685
DOI: 10.1016/j.conb.2018.12.013 -
Trends in Biochemical Sciences Feb 2017Alternative splicing is commonly believed to be a major source of cellular protein diversity. However, although many thousands of alternatively spliced transcripts are... (Review)
Review
Alternative splicing is commonly believed to be a major source of cellular protein diversity. However, although many thousands of alternatively spliced transcripts are routinely detected in RNA-seq studies, reliable large-scale mass spectrometry-based proteomics analyses identify only a small fraction of annotated alternative isoforms. The clearest finding from proteomics experiments is that most human genes have a single main protein isoform, while those alternative isoforms that are identified tend to be the most biologically plausible: those with the most cross-species conservation and those that do not compromise functional domains. Indeed, most alternative exons do not seem to be under selective pressure, suggesting that a large majority of predicted alternative transcripts may not even be translated into proteins.
Topics: Alternative Splicing; Exons; Protein Isoforms; Proteome; Proteomics
PubMed: 27712956
DOI: 10.1016/j.tibs.2016.08.008 -
Clinical and Translational Medicine Nov 2023Alternative splicing (AS) is an omnipresent regulatory mechanism of gene expression that enables the generation of diverse splice isoforms from a single gene. Recently,... (Review)
Review
BACKGROUND
Alternative splicing (AS) is an omnipresent regulatory mechanism of gene expression that enables the generation of diverse splice isoforms from a single gene. Recently, AS events have gained considerable momentum in the pathogenesis of inflammatory bowel disease (IBD).
METHODS
Our review has summarized the complex process of RNA splicing, and firstly highlighted the potential involved molecules that target aberrant splicing events in IBD. The quantitative transcriptome analyses such as microarrays, next-generation sequencing (NGS) for AS events in IBD have been also discussed.
RESULTS
Available evidence suggests that some abnormal splicing RNAs can lead to multiple intestinal disorders during the onset of IBD as well as the progression to colitis-associated cancer (CAC), including gut microbiota perturbations, intestinal barrier dysfunctions, innate/adaptive immune dysregulations, pro-fibrosis activation and some other risk factors. Moreover, current data show that the advanced technologies, including microarrays and NGS, have been pioneeringly employed to screen the AS candidates and elucidate the potential regulatory mechanisms of IBD. Besides, other biotechnological progresses such as the applications of third-generation sequencing (TGS), single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST), will be desired with great expectations.
CONCLUSIONS
To our knowledge, the current review is the first one to evaluate the potential regulatory mechanisms of AS events in IBD. The expanding list of aberrantly spliced genes in IBD along with the developed technologies provide us new clues to how IBD develops, and how these important AS events can be explored for future treatment.
Topics: Humans; Alternative Splicing; Inflammatory Bowel Diseases; RNA Splicing; Gastrointestinal Microbiome; Risk Factors
PubMed: 37983927
DOI: 10.1002/ctm2.1479 -
Chinese Medical Journal Jan 2020Alternative splicing can generate various structural and functional protein isoforms. Recently, accumulating evidence shows a relationship between alternative splicing... (Review)
Review
OBJECTIVE
Alternative splicing can generate various structural and functional protein isoforms. Recently, accumulating evidence shows a relationship between alternative splicing and cancer. Cancer is a complex and chronic disease that involves malignant transformation. In this review, we consider alternative splicing events in relation to the hallmarks of cancer cells, and discuss current therapies to treat cancer-related to alternative splicing.
DATA SOURCES
Data cited in this article are from the PubMed and Embase database, primarily focusing on research published from 2000 to 2018.
STUDY SELECTION
Articles were selected with the search terms "alternative splicing," "cancer cell," "tumor microenvironment," and "therapy."
RESULTS
Alternative splicing plays an important role in tumorigenesis, development, and escape from cell death. Taking this trait of cancer cells into consideration will allow more definite diagnoses of cancer, and allow the development of more effective medicines to intervene in cancer that could focus on controlling alternative splicing or competitively binding to the final products.
CONCLUSIONS
Alternative splicing is common in cancer cells. Consideration of alternative splicing may allow different strategies for cancer therapy or the identification of novel biomarkers for cancer diagnosis.
Topics: Alternative Splicing; Animals; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Protein Isoforms
PubMed: 31764175
DOI: 10.1097/CM9.0000000000000542 -
Nature Communications May 2022Autophagy and RNA alternative splicing are two evolutionarily conserved processes involved in overlapping physiological and pathological processes. However, the extent... (Review)
Review
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 with particular focus on disease relevance. The use of drugs targeting both alternative splicing and autophagy as well as the selective regulation of single autophagy-related protein isoforms, are considered as therapeutic strategies.
Topics: Alternative Splicing; Autophagy; Humans; Protein Isoforms; RNA; RNA Splicing
PubMed: 35585060
DOI: 10.1038/s41467-022-30433-1 -
Nature Communications Jan 2024Despite significant research, mechanisms underlying the failure of islet beta cells that result in type 2 diabetes (T2D) are still under investigation. Here, we report...
Despite significant research, mechanisms underlying the failure of islet beta cells that result in type 2 diabetes (T2D) are still under investigation. Here, we report that Sox9, a transcriptional regulator of pancreas development, also functions in mature beta cells. Our results show that Sox9-depleted rodent beta cells have defective insulin secretion, and aging animals develop glucose intolerance, mimicking the progressive degeneration observed in T2D. Using genome editing in human stem cells, we show that beta cells lacking SOX9 have stunted first-phase insulin secretion. In human and rodent cells, loss of Sox9 disrupts alternative splicing and triggers accumulation of non-functional isoforms of genes with key roles in beta cell function. Sox9 depletion reduces expression of protein-coding splice variants of the serine-rich splicing factor arginine SRSF5, a major splicing enhancer that regulates alternative splicing. Our data highlight the role of SOX9 as a regulator of alternative splicing in mature beta cell function.
Topics: Animals; Humans; Alternative Splicing; Diabetes Mellitus, Type 2; Insulin-Secreting Cells; Islets of Langerhans; RNA Splicing
PubMed: 38238288
DOI: 10.1038/s41467-023-44384-8 -
Plant Biotechnology Journal Aug 2021Among polyploid species with complex genomic architecture, variations in the regulation of alternative splicing (AS) provide opportunities for transcriptional and...
Among polyploid species with complex genomic architecture, variations in the regulation of alternative splicing (AS) provide opportunities for transcriptional and proteomic plasticity and the potential for generating trait diversities. However, the evolution of AS and its influence on grain development in diploid grass and valuable polyploid wheat crops are poorly understood. To address this knowledge gap, we developed a pipeline for the analysis of alternatively spliced transcript isoforms, which takes the high sequence similarity among polyploid wheat subgenomes into account. Through analysis of synteny and detection of collinearity of homoeologous subgenomes, conserved and specific AS events across five wheat and grass species were identified. A global analysis of the regulation of AS in diploid grass and polyploid wheat grains revealed diversity in AS events not only between the endosperm, pericarp and embryo overdevelopment, but also between subgenomes. Analysis of AS in homoeologous triads of polyploid wheats revealed evolutionary divergence between gene-level and transcript-level regulation of embryogenesis. Evolutionary age analysis indicated that the generation of novel transcript isoforms has occurred in young genes at a more rapid rate than in ancient genes. These findings, together with the development of comprehensive AS resources for wheat and grass species, advance understanding of the evolution of regulatory features of AS during embryogenesis and grain development in wheat.
Topics: Alternative Splicing; Embryonic Development; Evolution, Molecular; Genome, Plant; Polyploidy; Proteomics; Triticum
PubMed: 33706417
DOI: 10.1111/pbi.13579