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Cell Death and Differentiation Dec 2016Most human genes encode multiple mRNA variants and protein products through alternative splicing of exons and introns during pre-mRNA processing. In this way,... (Review)
Review
Most human genes encode multiple mRNA variants and protein products through alternative splicing of exons and introns during pre-mRNA processing. In this way, alternative splicing amplifies enormously the coding potential of the human genome and represents a powerful evolutionary resource. Nonetheless, the plasticity of its regulation is prone to errors and defective splicing underlies a large number of inherited and sporadic diseases, including cancer. One key cellular process affected by alternative splicing is the programmed cell death or apoptosis. Many apoptotic genes encode for splice variants having opposite roles in cell survival. This regulation modulates cell and tissue homeostasis and is implicated in both developmental and pathological processes. Furthermore, recent evidence has also unveiled splicing-mediated regulation of genes involved in autophagy, another essential process for tissue homeostasis. In this review, we highlight some of the best-known examples of alternative splicing events involved in cell survival. Emphasis is given to the role of this regulation in human cancer and in the response to chemotherapy, providing examples of how alternative splicing of apoptotic genes can be exploited therapeutically.
Topics: Alternative Splicing; Animals; Apoptosis; Cell Survival; Disease; Homeostasis; Humans; Neoplasms
PubMed: 27689872
DOI: 10.1038/cdd.2016.91 -
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 -
International Journal of Molecular... Apr 2019Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can... (Review)
Review
Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can have opposing functions and there are many instances whereby a splice isoform acts as an inhibitor of canonical isoform function, thereby adding an additional layer of regulation to important processes. Angiogenesis is an important process that is governed by alternative splicing mechanisms. This review focuses on the alternative spliced isoforms of key genes that are involved in the angiogenesis process; and .
Topics: Alternative Splicing; Angiopoietins; Animals; Humans; Neovascularization, Pathologic; Receptors, Vascular Endothelial Growth Factor
PubMed: 31027366
DOI: 10.3390/ijms20092067 -
International Journal of Molecular... Dec 2018RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, (eleven-nineteen lysine-rich leukemia gene 2) induction, and changes in... (Review)
Review
RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, (eleven-nineteen lysine-rich leukemia gene 2) induction, and changes in the levels of s. Endoplasmic reticulum stress induces the unfolded protein response comprising a highly conserved set of genes crucial for cell survival; among these is Ire1, whose auto-phosphorylation drives it to acquire a regulated mRNA decay activity. The mRNA-modifying function of phosphorylated Ire1 non-canonically splices Xbp1 mRNA and yet degrades other cellular mRNAs with related motifs. Naïve splenic B cells will activate Ire1 phosphorylation early on after lipopolysaccharide (LPS) stimulation, within 18 h; large-scale changes in mRNA content and splicing patterns result. Inhibition of the mRNA-degradation function of Ire1 is correlated with further differences in the splicing patterns and a reduction in the mRNA factors for snRNA transcription. Some of the >4000 splicing changes seen at 18 h after LPS stimulation persist into the late stages of antibody secretion, up to 72 h. Meanwhile some early splicing changes are supplanted by new splicing changes introduced by the up-regulation of ELL2, a transcription elongation factor. ELL2 is necessary for immunoglobulin secretion and does this by changing mRNA processing patterns of immunoglobulin heavy chain and >5000 other genes.
Topics: Alternative Splicing; Animals; B-Lymphocytes; Endoplasmic Reticulum Stress; Humans; RNA Splicing; RNA, Messenger; Unfolded Protein Response
PubMed: 30544499
DOI: 10.3390/ijms19123919 -
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 -
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 -
Science Advances Mar 2023Cohesin, a trimeric complex that establishes sister chromatid cohesion, has additional roles in chromatin organization and transcription. We report that among those...
Cohesin, a trimeric complex that establishes sister chromatid cohesion, has additional roles in chromatin organization and transcription. We report that among those roles is the regulation of alternative splicing through direct interactions and in situ colocalization with splicing factors. Degradation of cohesin results in marked changes in splicing, independent of its effects on transcription. Introduction of a single cohesin point mutation in embryonic stem cells alters splicing patterns, demonstrating causality. In primary human acute myeloid leukemia, mutations in cohesin are highly correlated with distinct patterns of alternative splicing. Cohesin also directly interacts with BRD4, another splicing regulator, to generate a pattern of splicing that is distinct from either factor alone, documenting their functional interaction. These findings identify a role for cohesin in regulating alternative splicing in both normal and leukemic cells and provide insights into the role of cohesin mutations in human disease.
Topics: Humans; Alternative Splicing; Nuclear Proteins; Transcription Factors; Cell Cycle Proteins; Cohesins
PubMed: 36857449
DOI: 10.1126/sciadv.ade3876 -
International Journal of Developmental... Dec 2016Alternative pre-mRNA splicing is a fundamental regulatory process for most mammalian multi-exon genes to increase proteome diversity. Nonsense-mediated mRNA decay (NMD)... (Review)
Review
Alternative pre-mRNA splicing is a fundamental regulatory process for most mammalian multi-exon genes to increase proteome diversity. Nonsense-mediated mRNA decay (NMD) is a conserved mRNA surveillance mechanism to mitigate deleterious effects caused by gene mutations or transcriptional errors. Coupling alternative splicing and NMD (AS-NMD), in which alternative splicing switches between translational and NMD isoforms, results in fine-tuning overall gene expression to, in turn, expand the functional activities of these two post-transcriptional regulatory processes. AS-NMD is known for maintaining homeostatic expression of many RNA-binding proteins. We further show that AS-NMD is a conserved mechanism among mammals to induce developmental expression of the synaptic scaffold protein PSD-95. Comparing gene sequences between human Psd-95 and its ancestral orthologues indicates that AS-NMD regulation of mammalian Psd-95 is a product of selective pressure and that it enforces neural-specific expression of PSD-95 proteins in mammals. Invertebrate homolog of Psd-95 is not subjected to AS-NMD regulation and its protein product does not exhibit neural-specific expression. Given the prevalence of alternative splicing regulation in the mammalian nervous system, neural-specific expression of many other genes could be controlled by AS-NMD in a similar manner. We discuss the implication of these discoveries, as well as the challenges in generalizing the regulation and functional activity of AS-NMD.
Topics: Alternative Splicing; Animals; Gene Expression; Humans; Neurons; Nonsense Mediated mRNA Decay; RNA, Messenger
PubMed: 26968265
DOI: 10.1016/j.ijdevneu.2016.03.003 -
Genes Sep 2023Alternative RNA splicing, a ubiquitous mechanism of gene regulation in eukaryotes, expands genome coding capacity and proteomic diversity. It has essential roles in all... (Review)
Review
Alternative RNA splicing, a ubiquitous mechanism of gene regulation in eukaryotes, expands genome coding capacity and proteomic diversity. It has essential roles in all aspects of human physiology, including immunity. This review highlights the importance of RNA alternative splicing in regulating immune T cell function. We discuss how mutations that affect the alternative splicing of T cell factors can contribute to abnormal T cell function and ultimately lead to autoimmune diseases. We also explore the potential applications of strategies that target the alternative splicing changes of T cell factors. These strategies could help design therapeutic approaches to treat autoimmune disorders and improve immunotherapy.
Topics: Humans; Alternative Splicing; RNA; Proteomics; T-Lymphocytes; TCF Transcription Factors
PubMed: 37895245
DOI: 10.3390/genes14101896 -
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