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Trends in Endocrinology and Metabolism:... Dec 2023The liver plays a key role in sensing nutritional and hormonal inputs to maintain metabolic homeostasis. Recent studies into pre-mRNA splicing and alternative splicing... (Review)
Review
The liver plays a key role in sensing nutritional and hormonal inputs to maintain metabolic homeostasis. Recent studies into pre-mRNA splicing and alternative splicing (AS) and their effects on gene expression have revealed considerable transcriptional complexity in the liver, both in health and disease. While the contribution of these mechanisms to cell and tissue identity is widely accepted, their role in physiological and pathological contexts within tissues is just beginning to be appreciated. In this review, we showcase recent studies on the splicing and AS of key genes in metabolic pathways in the liver, the effect of metabolic signals on the spliceosome, and therapeutic intervention points based on RNA splicing.
Topics: Humans; RNA Splicing; Alternative Splicing; Liver Diseases; Homeostasis
PubMed: 37673766
DOI: 10.1016/j.tem.2023.08.007 -
International Journal of Molecular... Jan 2023Advancements in genomics, bioinformatics, and genome editing have uncovered new dimensions in gene regulation. Post-transcriptional modifications by the alternative... (Review)
Review
Advancements in genomics, bioinformatics, and genome editing have uncovered new dimensions in gene regulation. Post-transcriptional modifications by the alternative splicing of mRNA transcripts are critical regulatory mechanisms of mammalian gene expression. In the heart, there is an expanding interest in elucidating the role of alternative splicing in transcriptome regulation. Substantial efforts were directed toward investigating this process in heart development and failure. However, few studies shed light on alternative splicing products and their dysregulation in congenital heart defects (CHDs). While elegant reports showed the crucial roles of RNA binding proteins (RBPs) in orchestrating splicing transitions during heart development and failure, the impact of RBPs dysregulation or genetic variation on CHDs has not been fully addressed. Herein, we review the current understanding of alternative splicing and RBPs' roles in heart development and CHDs. Wediscuss the impact of perinatal splicing transition and its dysregulation in CHDs. We further summarize the discoveries made of causal splicing variants in key transcription factors that are implicated in CHDs. An improved understanding of the roles of alternative splicing in heart development and CHDs may potentially inform novel preventive and therapeutic advancements for newborn infants with CHDs.
Topics: Animals; Infant; Infant, Newborn; Humans; Alternative Splicing; RNA Splicing; Heart Defects, Congenital; Heart; RNA, Messenger; Mammals
PubMed: 36675070
DOI: 10.3390/ijms24021555 -
Experimental & Molecular Medicine Apr 2023Cells produce multiple mRNAs through alternative splicing, which ensures proteome diversity. Because most human genes undergo alternative splicing, key components of... (Review)
Review
Cells produce multiple mRNAs through alternative splicing, which ensures proteome diversity. Because most human genes undergo alternative splicing, key components of signal transduction pathways are no exception. Cells regulate various signal transduction pathways, including those associated with cell proliferation, development, differentiation, migration, and apoptosis. Since proteins produced through alternative splicing can exhibit diverse biological functions, splicing regulatory mechanisms affect all signal transduction pathways. Studies have demonstrated that proteins generated by the selective combination of exons encoding important domains can enhance or attenuate signal transduction and can stably and precisely regulate various signal transduction pathways. However, aberrant splicing regulation via genetic mutation or abnormal expression of splicing factors negatively affects signal transduction pathways and is associated with the onset and progression of various diseases, including cancer. In this review, we describe the effects of alternative splicing regulation on major signal transduction pathways and highlight the significance of alternative splicing.
Topics: Humans; Alternative Splicing; RNA Precursors; RNA Splicing; Cell Differentiation; Proteins; Signal Transduction
PubMed: 37009804
DOI: 10.1038/s12276-023-00981-7 -
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 -
Cells Dec 2019During tumor progression, hypoxia, nutrient deprivation or changes in the extracellular environment (i.e., induced by anti-cancer drugs) elicit adaptive responses in... (Review)
Review
During tumor progression, hypoxia, nutrient deprivation or changes in the extracellular environment (i.e., induced by anti-cancer drugs) elicit adaptive responses in cancer cells. Cellular plasticity increases the chance that tumor cells may survive in a challenging microenvironment, acquire new mechanisms of resistance to conventional drugs, and spread to distant sites. Re-activation of stem pathways appears as a significant cause of cellular plasticity because it promotes the acquisition of stem-like properties through a profound phenotypic reprogramming of cancer cells. In addition, it is a major contributor to tumor heterogeneity, depending on the coexistence of phenotypically distinct subpopulations in the same tumor bulk. Several cellular mechanisms may drive this fundamental change, in particular, high-throughput sequencing technologies revealed a key role for alternative splicing (AS). Effectively, AS is one of the most important pre-mRNA processes that increases the diversity of transcriptome and proteome in a tissue- and development-dependent manner. Moreover, defective AS has been associated with several human diseases. However, its role in cancer cell plasticity and tumor heterogeneity remains unclear. Therefore, unravelling the intricate relationship between AS and the maintenance of a stem-like phenotype may explain molecular mechanisms underlying cancer cell plasticity and improve cancer diagnosis and treatment.
Topics: Adaptation, Physiological; Alternative Splicing; Antineoplastic Agents; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Neoplastic Stem Cells; Phenotype; Transcriptome; Tumor Microenvironment
PubMed: 31877720
DOI: 10.3390/cells9010034 -
BioMed Research International 2016In eukaryotes, genes are frequently interrupted with noncoding sequences named introns. Alternative splicing is a nuclear mechanism by which these introns are removed... (Review)
Review
In eukaryotes, genes are frequently interrupted with noncoding sequences named introns. Alternative splicing is a nuclear mechanism by which these introns are removed and flanking coding regions named exons are joined together to generate a message that will be translated in the cytoplasm. This mechanism is catalyzed by a complex machinery known as the spliceosome, which is conformed by more than 300 proteins and ribonucleoproteins that activate and regulate the precision of gene expression when assembled. It has been proposed that several genetic diseases are related to defects in the splicing process, including cancer. For this reason, natural products that show the ability to regulate splicing have attracted enormous attention due to its potential use for cancer treatment. Some microbial metabolites have shown the ability to inhibit gene splicing and the molecular mechanism responsible for this inhibition is being studied for future applications. Here, we summarize the main types of natural products that have been characterized as splicing inhibitors, the recent advances regarding molecular and cellular effects related to these molecules, and the applications reported so far in cancer therapeutics.
Topics: Alternative Splicing; Animals; Antineoplastic Agents; Fatty Alcohols; Humans; Mice; Neoplasms; Pyrans; Xenograft Model Antitumor Assays
PubMed: 27610372
DOI: 10.1155/2016/3681094 -
Aging Feb 2021Gastric cancer (GC) is a heterogeneous disease with different clinical manifestations and prognoses. Alternative splicing (AS) is a determinant of gene expression and...
Gastric cancer (GC) is a heterogeneous disease with different clinical manifestations and prognoses. Alternative splicing (AS) is a determinant of gene expression and contributes to protein diversity from a rather limited gene transcript in metazoans. AS events are associated with different aspects of cancer biology, including cell proliferation, apoptosis, invasion, etc. Here, we present a comprehensive analysis of the prognostic AS profile in GC. GC-specific AS (GCAS) events were analyzed, and overall survival-associated GCAS (OS-GCAS) events were verified among the genome-wide AS events identified in The Cancer Genome Atlas (TCGA) database. In total, 1,287 GCAS events of 837 genes and 173 OS-GCAS events of 130 genes were identified. The parental genes of OS-GCAS events were significantly enriched in the development of GC. Protein-protein interaction (PPI) and OS-GCAS-associated splicing factor (SF) interaction networks were constructed. Multivariate Cox regression analysis with least absolute shrinkage and selection operator (LASSO) penalty was performed to establish a prognostic risk formula, representing 23 OS-GCAS events. The low-risk group had better OS than the high-risk group and lower immune and stromal scores. Cox proportional hazard regression was applied to generate an AS-clinical integrated prognostic model with a considerable area under the curve (AUC) value in both the training and validation datasets. Our study provides a profile of OS-GCAS events and an AS-clinical nomogram to predict the prognosis of GC.
Topics: Adult; Alternative Splicing; Female; Humans; Male; Nomograms; Prognosis; Stomach Neoplasms
PubMed: 33612482
DOI: 10.18632/aging.202507 -
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 -
Biochimica Et Biophysica Acta. Gene... 2019Alternative splicing of pre-mRNA is an essential post- and co-transcriptional mechanism of gene expression regulation that produces multiple mature mRNA transcripts from... (Review)
Review
Alternative splicing of pre-mRNA is an essential post- and co-transcriptional mechanism of gene expression regulation that produces multiple mature mRNA transcripts from a single gene. Genetic mutations that affect splicing underlie numerous devastating diseases. The complexity of splicing regulation allows for multiple therapeutic approaches to correct disease-associated mis-splicing events. In this review, we first highlight recent findings from therapeutic strategies that have used splice switching antisense oligonucleotides and small molecules that bind directly to RNA. Second, we summarize different genetic and chemical approaches to target components of the spliceosome to correct splicing defects in pathological conditions. Finally, we present an overview of compounds that target kinases and accessory pathways that intersect with the splicing machinery. Advancements in the understanding of disease-specific defects caused by mis-regulation of alternative splicing will certainly increase the development of therapeutic options for the clinic. This article is part of a Special Issue entitled: RNA structure and splicing regulation edited by Francisco Baralle, Ravindra Singh and Stefan Stamm.
Topics: Alternative Splicing; Animals; Gene Expression Regulation; Humans; Oligonucleotides, Antisense; RNA Precursors; RNA, Messenger; Signal Transduction; Small Molecule Libraries
PubMed: 31271898
DOI: 10.1016/j.bbagrm.2019.06.006 -
Journal of Experimental Botany Apr 2018This article comments on: 2018. Thermopriming triggers splicing memory in Arabidopsis. Journal of Experimental Botany 2659–2675.
This article comments on: 2018. Thermopriming triggers splicing memory in Arabidopsis. Journal of Experimental Botany 2659–2675.
Topics: Alternative Splicing; Arabidopsis; Heat-Shock Response; Hot Temperature; RNA Splicing
PubMed: 29718462
DOI: 10.1093/jxb/ery111