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Nature Reviews. Neuroscience May 2016Alternative precursor-mRNA splicing is a key mechanism for regulating gene expression in mammals and is controlled by specialized RNA-binding proteins. The misregulation... (Review)
Review
Alternative precursor-mRNA splicing is a key mechanism for regulating gene expression in mammals and is controlled by specialized RNA-binding proteins. The misregulation of splicing is implicated in multiple neurological disorders. We describe recent mouse genetic studies of alternative splicing that reveal its critical role in both neuronal development and the function of mature neurons. We discuss the challenges in understanding the extensive genetic programmes controlled by proteins that regulate splicing, both during development and in the adult brain.
Topics: Alternative Splicing; Animals; Brain; Humans; Nerve Net; Nerve Tissue Proteins; Neurogenesis; Neurons
PubMed: 27094079
DOI: 10.1038/nrn.2016.27 -
Advances in Experimental Medicine and... 2019Alternative splicing, the process of removing introns and joining exons of pre-mRNA, is critical for growth, development, tissue homeostasis, and species diversity.... (Review)
Review
Alternative splicing, the process of removing introns and joining exons of pre-mRNA, is critical for growth, development, tissue homeostasis, and species diversity. Dysregulation of alternative splicing can initiate and drive disease. Aberrant alternative splicing has been shown to promote the "hallmarks of cancer" in both hematological and solid cancers. Of interest, recent work has focused on the role of alternative splicing in prostate cancer and prostate cancer health disparities. We will provide a review of prostate cancer health disparities involving the African American population, alternative RNA splicing, and alternative splicing in prostate cancer. Lastly, we will summarize our work on differential alternative splicing in prostate cancer disparities and its implications for disparate health outcomes and therapeutic targets.
Topics: Black or African American; Alternative Splicing; Drug Resistance; Health Status Disparities; Humans; Male; Prostatic Neoplasms
PubMed: 31576545
DOI: 10.1007/978-3-030-22254-3_10 -
Cell Reports Mar 2023The specification of synaptic properties is fundamental for the function of neuronal circuits. "Terminal selector" transcription factors coordinate terminal gene...
The specification of synaptic properties is fundamental for the function of neuronal circuits. "Terminal selector" transcription factors coordinate terminal gene batteries that specify cell-type-specific properties. Moreover, pan-neuronal splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell-type-specific loss-of-function studies to uncover the contribution of the RNA-binding protein SLM2 to hippocampal synapse specification. Focusing on pyramidal cells and somatostatin (SST)-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins. In the absence of SLM2, neuronal populations exhibit normal intrinsic properties, but there are non-cell-autonomous synaptic phenotypes and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner.
Topics: Alternative Splicing; Neurons; Synapses; Pyramidal Cells; Interneurons; Hippocampus
PubMed: 36862556
DOI: 10.1016/j.celrep.2023.112173 -
Cells, Tissues, Organs 2022Alternative splicing is an essential mechanism of gene regulation, giving rise to remarkable protein diversity in higher eukaryotes. Epithelial-mesenchymal transition... (Review)
Review
Alternative splicing is an essential mechanism of gene regulation, giving rise to remarkable protein diversity in higher eukaryotes. Epithelial-mesenchymal transition (EMT) is a developmental process that plays an essential role in metazoan embryogenesis. Recent studies have revealed that alternative splicing serves as a fundamental layer of regulation that governs cells to undergo EMT. In this review, we summarize recent findings on the functional impact of alternative splicing in EMT and EMT-associated activities. We then discuss the regulatory mechanisms that control alternative splicing changes during EMT.
Topics: Alternative Splicing; Animals; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; RNA-Binding Proteins
PubMed: 34348273
DOI: 10.1159/000518249 -
International Journal of Environmental... Apr 2010Gene expression studies have shown that expression patterns of several genes have changed during the development of alcoholism. Gene expression is regulated not only at... (Review)
Review
Gene expression studies have shown that expression patterns of several genes have changed during the development of alcoholism. Gene expression is regulated not only at the level of transcription but also through alternative splicing of pre-mRNA. In this review, we discuss some of the evidence suggesting that alternative splicing of candidate genes such as DRD2 (encoding dopamine D2 receptor) may form the basis of the mechanisms underlying the pathophysiology of alcoholism. These reports suggest that aberrant expression of splice variants affects alcohol sensitivities, and alcohol consumption also regulates alternative splicing. Thus, investigations of alternative splicing are essential for understanding the molecular events underlying the development of alcoholism.
Topics: Alcoholism; Alternative Splicing; Animals; Gene Expression Regulation; Humans
PubMed: 20617039
DOI: 10.3390/ijerph7041448 -
Wiley Interdisciplinary Reviews. RNA Jul 2018Defects in alternative splicing are frequently found in human tumors and result either from mutations in splicing-regulatory elements of specific cancer genes or from... (Review)
Review
Defects in alternative splicing are frequently found in human tumors and result either from mutations in splicing-regulatory elements of specific cancer genes or from changes in the regulatory splicing machinery. RNA splicing regulators have emerged as a new class of oncoproteins and tumor suppressors, and contribute to disease progression by modulating RNA isoforms involved in the hallmark cancer pathways. Thus, dysregulation of alternative RNA splicing is fundamental to cancer and provides a potentially rich source of novel therapeutic targets. Here, we review the alterations in splicing regulatory factors detected in human tumors, as well as the resulting alternatively spliced isoforms that impact cancer hallmarks, and discuss how they contribute to disease pathogenesis. RNA splicing is a highly regulated process and, as such, the regulators are themselves tightly regulated. Differential transcriptional and posttranscriptional regulation of splicing factors modulates their levels and activities in tumor cells. Furthermore, the composition of the tumor microenvironment can also influence which isoforms are expressed in a given cell type and impact drug responses. Finally, we summarize current efforts in targeting alternative splicing, including global splicing inhibition using small molecules blocking the spliceosome or splicing-factor-modifying enzymes, as well as splice-switching RNA-based therapeutics to modulate cancer-specific splicing isoforms. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing.
Topics: Alternative Splicing; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Small Molecule Libraries; Spliceosomes
PubMed: 29693319
DOI: 10.1002/wrna.1476 -
FASEB Journal : Official Publication of... Feb 2021ADAMTS proteases mediate biosynthesis and breakdown of secreted extracellular matrix (ECM) molecules in numerous physiological and disease processes. In addition to...
ADAMTS proteases mediate biosynthesis and breakdown of secreted extracellular matrix (ECM) molecules in numerous physiological and disease processes. In addition to their catalytic domains, ADAMTS proteases contain ancillary domains, which mediate substrate recognition and ECM binding and confer distinctive properties and roles to individual ADAMTS proteases. Although alternative splicing can greatly expand the structural and functional diversity of ADAMTS proteases, it has been infrequently reported and functional consequences have been rarely investigated. Here, we characterize the structural and functional impact of alternative splicing of ADAMTS17, mutations in which cause Weill-Marchesani syndrome 4. Two novel ADAMTS17 splice variants, ADAMTS17A and ADAMTS17B, were investigated by structural modeling, mass spectrometry, and biochemical approaches. Our results identify a novel disulfide-bridged insertion in the ADAMTS17A spacer that originates from inclusion of a novel exon. This insertion results in differential autoproteolysis of ADAMTS17, and thus, predicts altered proteolytic activity against other substrates. The second variant, ADAMTS17B, results from an in-frame exon deletion and prevents ADAMTS17B secretion. Thus, alternative splicing of the ADAMTS spacer significantly regulates the physiologically relevant proteolytic activity of ADAMTS17, either by altering proteolytic specificity (ADAMTS17A) or by altering cellular localization (ADAMTS17B).
Topics: ADAMTS Proteins; Alternative Splicing; Blotting, Western; Coculture Techniques; Extracellular Matrix; Fibrillin-1; HEK293 Cells; Humans; Mass Spectrometry; Microfibrils; Mutation
PubMed: 33484187
DOI: 10.1096/fj.202001120RR -
Annual Review of Biomedical Data Science Aug 2023Alternative splicing is pivotal to the regulation of gene expression and protein diversity in eukaryotic cells. The detection of alternative splicing events requires... (Review)
Review
Alternative splicing is pivotal to the regulation of gene expression and protein diversity in eukaryotic cells. The detection of alternative splicing events requires specific omics technologies. Although short-read RNA sequencing has successfully supported a plethora of investigations on alternative splicing, the emerging technologies of long-read RNA sequencing and top-down mass spectrometry open new opportunities to identify alternative splicing and protein isoforms with less ambiguity. Here, we summarize improvements in short-read RNA sequencing for alternative splicing analysis, including percent splicing index estimation and differential analysis. We also review the computational methods used in top-down proteomics analysis regarding proteoform identification, including the construction of databases of protein isoforms and statistical analyses of search results. While many improvements in sequencing and computational methods will result from emerging technologies, there should be future endeavors to increase the effectiveness, integration, and proteome coverage of alternative splicing events.
Topics: Proteomics; Transcriptome; Protein Isoforms; Alternative Splicing; RNA Splicing
PubMed: 37561601
DOI: 10.1146/annurev-biodatasci-020722-044021 -
Cell Reports Apr 2023During intravasation, cancer cells cross the endothelial barrier and enter the circulation. Extracellular matrix stiffening has been correlated with tumor metastatic...
During intravasation, cancer cells cross the endothelial barrier and enter the circulation. Extracellular matrix stiffening has been correlated with tumor metastatic potential; however, little is known about the effects of matrix stiffness on intravasation. Here, we utilize in vitro systems, a mouse model, specimens from patients with breast cancer, and RNA expression profiles from The Cancer Genome Atlas Program (TCGA) to investigate the molecular mechanism by which matrix stiffening promotes tumor cell intravasation. Our data show that heightened matrix stiffness increases MENA expression, which promotes contractility and intravasation through focal adhesion kinase activity. Further, matrix stiffening decreases epithelial splicing regulatory protein 1 (ESRP1) expression, which triggers alternative splicing of MENA, decreases the expression of MENA, and enhances contractility and intravasation. Altogether, our data indicate that matrix stiffness regulates tumor cell intravasation through enhanced expression and ESRP1-mediated alternative splicing of MENA, providing a mechanism by which matrix stiffness regulates tumor cell intravasation.
Topics: Animals; Female; Humans; Mice; Alternative Splicing; Breast Neoplasms; Cell Line, Tumor; RNA-Binding Proteins
PubMed: 37027295
DOI: 10.1016/j.celrep.2023.112338 -
PeerJ 2023Sexually dimorphic traits are common in sexually reproducing organisms and can be encoded by differential gene regulation between males and females. Although alternative...
Sexually dimorphic traits are common in sexually reproducing organisms and can be encoded by differential gene regulation between males and females. Although alternative splicing is common mechanism in generating transcriptional diversity, its role in generating sex differences relative to differential gene expression is less clear. Here, we investigate the relative roles of differential gene expression and alternative splicing between male and female the horseshoe bat species, . Horseshoe bats are an excellent model to study acoustic differences between sexes. Using RNA-seq analyses of two somatic tissues (brain and liver) from males and females of the same population, we identified 3,471 and 2,208 differentially expressed genes between the sexes (DEGs) in the brain and liver, respectively. DEGs were enriched with functional categories associated with physiological difference of the sexes (e.g.,gamete generation and energy production for reproduction in females). In addition, we also detected many differentially spliced genes between the sexes (DSGs, 2,231 and 1,027 in the brain and liver, respectively) which were mainly involved in regulation of RNA splicing and mRNA metabolic process. Interestingly, we found a significant enrichment of DEGs on the X chromosome, but not for DSGs. As for the extent of overlap between the two sets of genes, more than expected overlap of DEGs and DSGs was observed in the brain but not in the liver. This suggests that more complex tissues, such as the brain, may require the intricate and simultaneous interplay of both differential gene expression and splicing of genes to govern sex-specific functions. Overall, our results support that variation in gene expression and alternative splicing are important and complementary mechanisms governing sex differences.
Topics: Animals; Female; Male; Alternative Splicing; Chiroptera; Gene Expression; Sex Characteristics
PubMed: 37123006
DOI: 10.7717/peerj.15231