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Stem Cell Research & Therapy May 2018α6-Integrin subunit (also known as CD49f) is a stemness signature that has been found on the plasma membrane of more than 30 stem cell populations. A growing body of... (Review)
Review
α6-Integrin subunit (also known as CD49f) is a stemness signature that has been found on the plasma membrane of more than 30 stem cell populations. A growing body of studies have focused on the critical role of α6-containing integrins (α6β1 and α6β4) in the regulation of stem cell properties, lineage-specific differentiation, and niche interaction. α6-Integrin subunit can be alternatively spliced at the post-transcriptional level, giving rise to divergent isoforms which differ in the cytoplasmic and/or extracellular domains. The cytoplasmic domain of integrins is an important functional part of integrin-mediated signals. Structural changes in the cytoplasmic domain of α6 provide an efficient means for the regulation of stem cell responses to biochemical stimuli and/or biophysical cues in the stem cell niche, thus impacting stem cell fate determination. In this review, we summarize the current knowledge on the structural variants of the α6-integrin subunit and spatiotemporal expression of α6 cytoplasmic variants in embryonic and adult stem/progenitor cells. We highlight the roles of α6 cytoplasmic variants in stem cell fate decision and niche interaction, and discuss the potential mechanisms involved. Understanding of the distinct functions of α6 splicing variants in stem cell biology may inform the rational design of novel stem cell-based therapies for a range of human diseases.
Topics: Alternative Splicing; Cell Differentiation; Humans; Integrin alpha6; Stem Cells
PubMed: 29720266
DOI: 10.1186/s13287-018-0868-3 -
International Journal of Molecular... Oct 2021Alternative RNA splicing is an important regulatory process used by genes to increase their diversity. This process is mainly executed by specific classes of RNA binding... (Review)
Review
Alternative RNA splicing is an important regulatory process used by genes to increase their diversity. This process is mainly executed by specific classes of RNA binding proteins that act in a dosage-dependent manner to include or exclude selected exons in the final transcripts. While these processes are tightly regulated in cells and tissues, little is known on how the dosage of these factors is achieved and maintained. Several recent studies have suggested that alternative RNA splicing may be in part modulated by microRNAs (miRNAs), which are short, non-coding RNAs (~22 nt in length) that inhibit translation of specific mRNA transcripts. As evidenced in tissues and in diseases, such as cancer and neurological disorders, the dysregulation of miRNA pathways disrupts downstream alternative RNA splicing events by altering the dosage of splicing factors involved in RNA splicing. This attractive model suggests that miRNAs can not only influence the dosage of gene expression at the post-transcriptional level but also indirectly interfere in pre-mRNA splicing at the co-transcriptional level. The purpose of this review is to compile and analyze recent studies on miRNAs modulating alternative RNA splicing factors, and how these events contribute to transcript rearrangements in tissue development and disease.
Topics: Alternative Splicing; Animals; Gene Expression; Humans; MicroRNAs; RNA Interference; Transcription, Genetic
PubMed: 34769047
DOI: 10.3390/ijms222111618 -
Planta Jun 2013Transcription factors play a central role in the gene regulatory networks that mediate various aspects of plant developmental processes and responses to environmental... (Review)
Review
Transcription factors play a central role in the gene regulatory networks that mediate various aspects of plant developmental processes and responses to environmental changes. Therefore, their activities are elaborately regulated at multiple steps. In particular, accumulating evidence illustrates that post-transcriptional control of mRNA metabolism is a key molecular scheme that modulates the transcription factor activities in plant responses to temperature fluctuations. Transcription factors have a modular structure consisting of distinct protein domains essential for DNA binding, dimerization, and transcriptional regulation. Alternative splicing produces multiple proteins having different structural domain compositions from a single transcription factor gene. Recent studies have shown that alternative splicing of some transcription factor genes generates small interfering peptides (siPEPs) that negatively regulate the target transcription factors via peptide interference (PEPi), constituting self-regulatory circuits in plant cold stress response. A number of splicing factors, which are involved in RNA binding, splice site selection, and spliceosome assembly, are also affected by temperature fluctuations, supporting the close association of alternative splicing of transcription factors with plant responses to low temperatures. In this review, we summarize recent progress on the temperature-responsive alternative splicing of transcription factors in plants with emphasis on the siPEP-mediated PEPi mechanism.
Topics: Alternative Splicing; Cold Temperature; Peptides; Plants; Stress, Physiological; Transcription Factors
PubMed: 23624977
DOI: 10.1007/s00425-013-1882-4 -
Brain : a Journal of Neurology Feb 2024The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3,...
The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease. We sought to address these knowledge gaps through a comprehensive study of 29 publicly available RNA-sequencing datasets. We identified that dysregulation of alternative splicing is widespread across CAG expansion mouse models of SCAs 1, 3 and 7. These changes were detected presymptomatically, persisted throughout disease progression, were repeat length-dependent, and were present in brain regions implicated in SCA pathogenesis including the cerebellum, pons and medulla. Across disease progression, changes in alternative splicing occurred in genes that function in pathways and processes known to be impaired in SCAs, such as ion channels, synaptic signalling, transcriptional regulation and the cytoskeleton. We validated several key alternative splicing events with known functional consequences, including Trpc3 exon 9 and Kcnma1 exon 23b, in the Atxn1154Q/2Q mouse model. Finally, we demonstrated that alternative splicing dysregulation is responsive to therapeutic intervention in CAG expansion SCAs with Atxn1 targeting antisense oligonucleotide rescuing key splicing events. Taken together, these data demonstrate that widespread presymptomatic dysregulation of alternative splicing in CAG expansion SCAs may contribute to disease onset, early neuronal dysfunction and may represent novel biomarkers across this devastating group of neurodegenerative disorders.
Topics: Animals; Mice; Alternative Splicing; Spinocerebellar Ataxias; Cerebellum; Mutation; Disease Progression; Trinucleotide Repeat Expansion; Olivopontocerebellar Atrophies
PubMed: 37776516
DOI: 10.1093/brain/awad329 -
BMC Bioinformatics Nov 2005Alternative splicing is a major mechanism of generating protein diversity in higher eukaryotes. Although at least half, and probably more, of mammalian genes are...
BACKGROUND
Alternative splicing is a major mechanism of generating protein diversity in higher eukaryotes. Although at least half, and probably more, of mammalian genes are alternatively spliced, it was not clear, whether the frequency of alternative splicing is the same in different functional categories. The problem is obscured by uneven coverage of genes by ESTs and a large number of artifacts in the EST data.
RESULTS
We have developed a method that generates possible mRNA isoforms for human genes contained in the EDAS database, taking into account the effects of nonsense-mediated decay and translation initiation rules, and a procedure for offsetting the effects of uneven EST coverage. Then we computed the number of mRNA isoforms for genes from different functional categories. Genes encoding ribosomal proteins and genes in the category "Small GTPase-mediated signal transduction" tend to have fewer isoforms than the average, whereas the genes in the category "DNA replication and chromosome cycle" have more isoforms than the average. Genes encoding proteins involved in protein-protein interactions tend to be alternatively spliced more often than genes encoding non-interacting proteins, although there is no significant difference in the number of isoforms of alternatively spliced genes.
CONCLUSION
Filtering for functional isoforms satisfying biological constraints and accounting for uneven EST coverage allowed us to describe differences in alternative splicing of genes from different functional categories. The observations seem to be consistent with expectations based on current biological knowledge: less isoforms for ribosomal and signal transduction proteins, and more alternative splicing of interacting and cell cycle proteins.
Topics: Algorithms; Alternative Splicing; Chromosome Mapping; Codon, Initiator; Computers, Molecular; Humans; Protein Biosynthesis; Protein Isoforms; RNA, Messenger; Software
PubMed: 16274476
DOI: 10.1186/1471-2105-6-266 -
Genes Jul 2021Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene... (Review)
Review
Almost all transcribed human genes undergo alternative RNA splicing, which increases the diversity of the coding and non-coding cellular landscape. The resultant gene products might have distinctly different and, in some cases, even opposite functions. Therefore, the abnormal regulation of alternative splicing plays a crucial role in malignant transformation, development, and progression, a fact supported by the distinct splicing profiles identified in both healthy and tumor cells. Drug resistance, resulting in treatment failure, still remains a major challenge for current cancer therapy. Furthermore, tumor cells often take advantage of aberrant RNA splicing to overcome the toxicity of the administered chemotherapeutic agents. Thus, deciphering the alternative RNA splicing variants in tumor cells would provide opportunities for designing novel therapeutics combating cancer more efficiently. In the present review, we provide a comprehensive outline of the recent findings in alternative splicing in the most common neoplasms, including lung, breast, prostate, head and neck, glioma, colon, and blood malignancies. Molecular mechanisms developed by cancer cells to promote oncogenesis as well as to evade anticancer drug treatment and the subsequent chemotherapy failure are also discussed. Taken together, these findings offer novel opportunities for future studies and the development of targeted therapy for cancer-specific splicing variants.
Topics: Alternative Splicing; Antineoplastic Agents; Carcinogenesis; Drug Resistance, Neoplasm; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Protein Isoforms; RNA; RNA Splicing; RNA, Messenger
PubMed: 34356101
DOI: 10.3390/genes12071085 -
Virologica Sinica Apr 2023• The first global exploration of alternative splicing changes in COVID-19 and relevant respiratory diseases. • The specificities and similarities between...
• The first global exploration of alternative splicing changes in COVID-19 and relevant respiratory diseases. • The specificities and similarities between alternative splicing events in different respiratory diseases. • Identification of regulatory network of RBP and alternative splicing in respiratory diseases. • Defining the interactions of alternative splicing and cell abundance in respiratory diseases.
Topics: Humans; Alternative Splicing; COVID-19; Computational Biology; Blood Cells
PubMed: 36690184
DOI: 10.1016/j.virs.2023.01.007 -
Bioinformatics (Oxford, England) Jun 2016Understanding the occurrence and regulation of alternative splicing (AS) is a key task towards explaining the regulatory processes that shape the complex transcriptomes...
MOTIVATION
Understanding the occurrence and regulation of alternative splicing (AS) is a key task towards explaining the regulatory processes that shape the complex transcriptomes of higher eukaryotes. With the advent of high-throughput sequencing of RNA (RNA-Seq), the diversity of AS transcripts could be measured at an unprecedented depth. Although the catalog of known AS events has grown ever since, novel transcripts are commonly observed when working with less well annotated organisms, in the context of disease, or within large populations. Whereas an identification of complete transcripts is technically challenging and computationally expensive, focusing on single splicing events as a proxy for transcriptome characteristics is fruitful and sufficient for a wide range of analyses.
RESULTS
We present SplAdder, an alternative splicing toolbox, that takes RNA-Seq alignments and an annotation file as input to (i) augment the annotation based on RNA-Seq evidence, (ii) identify alternative splicing events present in the augmented annotation graph, (iii) quantify and confirm these events based on the RNA-Seq data and (iv) test for significant quantitative differences between samples. Thereby, our main focus lies on performance, accuracy and usability.
AVAILABILITY
Source code and documentation are available for download at http://github.com/ratschlab/spladder Example data, introductory information and a small tutorial are accessible via http://bioweb.me/spladder
CONTACTS
: [email protected] or [email protected]
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Alternative Splicing; Gene Expression Profiling; RNA; Sequence Analysis, RNA; Transcriptome
PubMed: 26873928
DOI: 10.1093/bioinformatics/btw076 -
Cell Reports Dec 2020Multi-input logic gene circuits can enable sophisticated control of cell function, yet large-scale synthetic circuitry in mammalian cells has relied on...
Multi-input logic gene circuits can enable sophisticated control of cell function, yet large-scale synthetic circuitry in mammalian cells has relied on post-transcriptional regulation or recombinase-triggered state transitions. Large-scale transcriptional logic, on the other hand, has been challenging to implement. Inspired by a naturally found regulatory strategy of using multiple alternative promoters, followed by alternative splicing, we developed a scalable and compact platform for transcriptional OR logic using inputs to those promoters. The platform is extended to implement disjunctive normal form (DNF) computations capable of implementing arbitrary logic rules. Specifically, AND logic is implemented at individual promoters using synergistic transcriptional inputs, and NOT logic via microRNA inputs targeting unique exon sequences driven by those promoters. Together, these regulatory programs result in DNF-like logic control of output gene expression. The approach offers flexibility for building complex logic programs in mammalian cells.
Topics: Alternative Splicing; Animals; Humans; Mammals; Synthetic Biology
PubMed: 33264624
DOI: 10.1016/j.celrep.2020.108437 -
Cell May 2002Alternative splicing is an important means of regulating the expression of eukaryotic genes and enhancing protein diversity. A detailed examination of the Drosophila... (Review)
Review
Alternative splicing is an important means of regulating the expression of eukaryotic genes and enhancing protein diversity. A detailed examination of the Drosophila Sex-lethal gene has led to two significant discoveries-the role of the splicing factor SPF45 in defining the site of exon ligation, and that alternative splicing can be regulated at the second step.
Topics: Alternative Splicing; Animals; Drosophila Proteins; Eukaryotic Cells; Gene Expression Regulation; Humans; Mutation; RNA Splicing Factors; RNA, Messenger; RNA-Binding Proteins; Sex Determination Processes
PubMed: 12086596
DOI: 10.1016/s0092-8674(02)00750-x