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Major alternative splicing events in the metazoan transcriptome. Major types of alternative splicing events are shown. Brown boxes indicate constitutive exons, while boxes in other colors indicate alternative spliced exons.
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Alternative splicing (AS) is an essential mechanism in post-transcriptional regulation and leads to protein diversity. It has been shown that AS is prevalent in metazoan genomes, and the splicing pattern is dynamically regulated in different tissues and cell types, including embryonic stem cells. These observations suggest that AS may play critical...
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Context 1
... is primarily regulated by approximately 200 RNA-binding proteins (splicing factors) together with a basal spliceosome through direct recognition of short sequence motifs near exon/ intron boundaries [13] . Depending on the pattern of exon inclusion/skipping, AS events can be categorized into at least six major types, including cassette exon skipping, mutually exclusive exons, alternative 5' splice site selection, alternative 3' splice site selection, alternative retained intron, and tandem cassette ( Figure 1). There are more complex patterns but they are much fewer in number than these major types, therefore most analyses of AS events focus on these six types, particularly cassette exon skipping which represents the majority of AS events. ...
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... that have ESC-specific isoforms are particularly intriguing. A study conducted by Gabut et al [94] used microarray profiling to compare patterns of AS in undifferentiated and differentiated hESCs, and identified an evolutionarily conserved ESC-specific AS event of the gene FOXP1 (Forkhead box transcription factor 1). Experimental validation showed that inclusion of FOXP1 exon 18b is specific to self-renewing, pluripotent hESCs, thus this transcript isoform was named "FOXP1-ES". ...
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Purpose of Review
Our understanding of the biology of hematopoietic stem cells is evolving beyond hierarchical models and markers of stem cell purification to a far more fluid model wherein degrees of multipotency of individual cells can change over time. This review is to outline these new concepts:
Recent Findings
The long-term repopulating hema...
Citations
... Recent work in this area is beginning to illuminate codon usage differences between proliferating and differentiating cell states 29,108,109 and even within stem cell lineages 18,110 . In stem cells, post-transcriptional control of gene expression is critical to promote transitions from progenitor to differentiated states [111][112][113][114] . Such regulation seems especially crucial in neural stem cells [115][116][117] . ...
Regulation of codon optimality is an increasingly appreciated layer of cell- and tissue-specific protein expression control. Here, we use codon-modified reporters to show that differentiation of Drosophila neural stem cells into neurons enables protein expression from rare-codon-enriched genes. From a candidate screen, we identify the cytoplasmic polyadenylation element binding (CPEB) protein Orb2 as a positive regulator of rare-codon-dependent mRNA stability in neurons. Using RNA sequencing, we reveal that Orb2-upregulated mRNAs in the brain with abundant Orb2 binding sites have a rare-codon bias. From these Orb2-regulated mRNAs, we demonstrate that rare-codon enrichment is important for mRNA stability and social behavior function of the metabotropic glutamate receptor (mGluR). Our findings reveal a molecular mechanism by which neural stem cell differentiation shifts genetic code regulation to enable critical mRNA stability and protein expression.
... In contrast, inhibitory factors like hnRNP proteins preferentially bind to intronic or exonic splicing silencers (ISS and ESS, respectively) ( Figure 1b) [9,22]. The methods of alternative splicing mainly include exon skipping, alternative 5 ′ SS selection, alternative 3 ′ SS selection, mutually exclusive splicing, retained intron, alternative promoters, and alternative polyA [23][24][25][26]. Exon skipping is caused by the splicing of the exon and its two flanking introns from the transcript (Figure 2b), and is the most common alternative splicing method in mammals [27]. ...
Mycobacterium tuberculosis (Mtb) is one of the major causes of human death. In its battle with humans, Mtb has fully adapted to its host and developed ways to evade the immune system. At the same time, the human immune system has developed ways to respond to Mtb. The immune system responds to viral and bacterial infections through a variety of mechanisms, one of which is alternative splicing. In this study, we summarized the overall changes in alternative splicing of the transcriptome after macrophages were infected with Mtb. We found that after infection with Mtb, cells undergo changes, including (1) directly reducing the expression of splicing factors, which affects the regulation of gene expression, (2) altering the original function of proteins through splicing, which can involve gene truncation or changes in protein domains, and (3) expressing unique isoforms that may contribute to the identification and development of tuberculosis biomarkers. Moreover, alternative splicing regulation of immune-related genes, such as IL-4, IL-7, IL-7R, and IL-12R, may be an important factor affecting the activation or dormancy state of Mtb. These will help to fully understand the immune response to Mtb infection, which is crucial for the development of tuberculosis biomarkers and new drug targets.
... Specifically, these variants occur in the sequences of nucleotides that direct the removal of introns (non-coding regions) and the joining of exons (coding regions) to form mature messenger RNA. Splice variants can lead to the production of abnormal or truncated proteins, with potentially altered functional properties, that may have a significant impact on cell biology and tumorigenesis (Chen et al., 2015). ...
Introduction: Medullary thyroid carcinoma (MTC) is an aggressive cancer that is often caused by driver mutations in RET. Splice site variants (SSV) reflect changes in mRNA processing, which may alter protein function. RET SSVs have been described in thyroid tumors in general but have not been extensively studied in MTC.
Methods: The prevalence of RET SSVs was evaluated in 3,624 cases with next generation sequence reports, including 25 MTCs. Fisher exact analysis was performed to compare RET SSV frequency in cancers with/without a diagnosis of MTC.
Results: All 25 MTCs had at least one of the two most common RET SSVs versus 0.3% of 3,599 cancers with other diagnoses (p < 0.00001). The 11 cancers with non-MTC diagnoses that had the common RET SSVs were 4 neuroendocrine cancers, 4 non-small cell lung carcinomas, 2 non-MTC thyroid cancers, and 1 melanoma. All 25 MTCs analyzed had at least one of the two most common RET SSVs, including 4 with no identified mutational driver.
Discussion: The identification of RET SSVs in all MTCs, but rarely in other cancer types, demonstrates that these RET SSVs distinguish MTCs from other cancer types. Future studies are needed to investigate whether these RET SSVs play a pathogenic role in MTC.
... Based on this analysis, the observed modi cations could amplify the activity of exon 7, in which the missense mutation was identi ed. This ampli cation has potential implications for alternative splicing mechanisms, resulting in a range of outcomes such as a production of aberrant mRNA transcripts, changes in mRNA stability, and a generation of varied protein isoforms, some of which might be non-functional or exhibit modi ed functions (Fig. 5b) [47]. Noteworthy, to note the results of the effect of missense mutation on other positions of the protein (Supplementary Table 2 (Fig. 6a), depicts a spectrum: while some tools indicate its benign nature, others like I-Mutant Disease (IR 6) and HOPE (score 1.14*10 − 6) point towards its potential pathogenicity. ...
Hereditary angioedema (HAE) is a complex genetic disorder characterized by recurrent episodes of localized skin and mucosal swelling, with potential life-threatening complications, particularly in the upper respiratory tract. While much is understood about the mutations behind HAE I-II types, the genetic landscape of type III remains complex. Our study provides a comprehensive exploration of an undiagnosed case of a 13-year-old female presenting with HAE symptoms. Despite undergoing thorough clinical evaluations including blood, immunochemical, coprological, and allergen tests, no correlations with allergies or HAE I-II types were observed. Leveraging whole-exome sequencing, a unique missense mutation in the F12 gene (NC_000005.9: g.176831826 C > G, Ala207Pro) was identified in the patient's genetic profile, which she inherited from both parents. Subsequent comprehensive in silico analyses suggest this mutation could be a potent contributor to HAE's III type manifestation, notably in homozygous females. The data brought forth intricate relationships between age-related hormonal changes (estrogen fluctuations), specific genetic variance, and the multifaceted bradykinin pathway's involvement in HAE episodes. Significantly, the mutation's position within the EGF-like 2 domain hints at possible effects on protein structure, which might impact its structural stability and subsequent function. Advanced bioinformatics approaches greatly streamlined the identification and comprehension of this pathogenic mutation, demonstrating their invaluable role, especially in atypical cases. We believe that merging in silico methodologies with clinical observations offers a promising avenue for a comprehensive understanding of genetic disorders, emphasizing an integrated approach essential for the development of personalized diagnostic and treatment approaches for diseases such as HAE.
... It has been shown extensively in the context of embryonic stem cells and induced pluripotent stem cells that alternative splicing is tightly associated their ability to maintain stemness and control differentiation. 38 Moreover, alternative pre-mRNA splicing has been implicated in the specification of the hematopoietic lineage and development 39,40 and neurogenesis and brain development. 41 Therefore, a role for alternative splicing in the control of satellite cell activation is consistent with its observed function in other tissue systems. ...
Coactivator-associated arginine methyltransferase 1 (CARM1) is a methyltransferase whose function has been highly studied in the context of nuclear receptor signaling. However, CARM1 is known to epigenetically regulate expression of several myogenic genes involved in differentiation such as Myog and MEF2C. CARM1 also acts to regulate myogenesis through its influence on various cellular processes from embryonic to adult myogenesis. First, CARM1 has a crucial role in establishing polarity-regulated gene expression during an asymmetric satellite cell division by methylating PAX7, leading to the expression of Myf5. Second, satellite cells express the CARM1-FL and CARM1-ΔE15 isoforms. The former has been shown to promote pre-mRNA splicing through its interaction with CA150 and U1C, leading to their methylation and increased activity, while the latter displays a reduction in both metrics, thus, modulating alternative pre-mRNA splice forms in muscle cells. Third, CARM1 is a regulator of autophagy through its positive reinforcement of AMPK activity and gene expression. Autophagy already has known implications in ageing and disease, and CARM1 could follow suite. Thus, CARM1 is a central regulator of several important processes impacting muscle stem cell function and myogenesis.
... It can increase the diversity of mRNAs expressed from the genome and is a source of increase in genomic expression and organism complexity 16,17 . As a core element of gene regulation, it is involved in almost all biological processes, such as cell proliferation, growth, differentiation, metabolism, apoptosis and signal transduction 18,19 , and previous studies have shown that it is also related to lactation 20,21 . From the perspective of protein products, there are two main types of alternative splicing: one is the splicing that leads to insertion or deletion, and the other is the splicing that leads to exon substitutions 22 . ...
Liver X receptor α (LXRα) is a ligand-dependent transcription factor and plays an important role in the regulation of cholesterol homeostasis, fatty acid biosynthesis and glucose metabolism. In this study, transcripts of LXRα gene were cloned and characterized from buffalo mammary gland, and three alternative splicing transcripts of buffalo LXRα gene were identified, named LXRα1, LXRα2 and LXRα3. The structure of the LXRα transcripts of buffalo and cattle was highly similar. Bioinformatics analysis showed that LXRα1 contains two complete functional domains of LXRα, one is the DNA-binding domain (NR_DBD_LXR) and the other is the ligand-binding domain (NR_LBD_LXR). The reading frame of LXRα2 is altered due to the skipping of exon 9, which truncates its encoding protein prematurely at the 400th amino acid residue, making it contain a complete DNA-binding domain and part of a ligand-binding domain. Due to the deletion of exon 4, the protein encoded by LXRα3 lacks 89 amino acid residues and contains only a complete ligand-binding domain, which makes it lose its transcriptional regulation function. In addition, motifs and conserved domains of three LXRα variants of buffalo were highly consistent with those of corresponding transcripts from other mammal species. Subcellular localization analysis showed that LXRα1 plays a functional role in the nucleus of buffalo mammary epithelial cells, while LXRα2 and LXRα3 are distributed in the nucleus and cytoplasm. Compared with non-lactating period, the mRNA abundance of the three LXRα transcripts in the mammary gland tissue of buffalo increased during lactating period, revealing that they play a key role in the synthesis of buffalo milk fat. Among the three LXRα transcripts, LXRα1 has the highest expression in the mammary gland, indicating that it is the major transcript in the mammary gland and has important regulatory functions, while LXRα2 and LXRα3 may have regulatory effects on the function of LXRα1. This study highlights the key role of LXRα alternative splicing in the post-transcriptional regulation of buffalo lactation.
... Таким чином, один ген може породжувати не одну, а кілька протеїнових ізоформ. Альтернативний сплайсинг регулюється приблизно 200 РНКзв'язуючими протеїнами -факторами сплайсингу [1,2,7,25]. Результати досліджень, проведених з використанням методів секвенування, свідчать про те, що пре-мРНК більше 90 % генів людини піддаються альтернативному сплайсингу [21]. ...
The scientific review presents the mechanisms of action of intranuclear miRNAs, namely microRNA-mediated regulation of the non-coding RNA (ncRNA) transcriptome and alternative splicing. To write the article, information was searched using Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library, CyberLeninka databases. It is emphasized that a significant effect on the composition of the transcriptome is provided by microRNAs in the RNA-induced silencing complex that induce posttranscriptional degradation of long ncRNAs localized in the cell nucleus. Scientists believe that long ncRNAs are involved in the epigenetic regulation of gene silencing through chromatin remodeling. It is shown that long ncRNAs are actively involved in the development of some liver diseases. It is reported that the most important mechanism for expanding the spectrum of the transcriptome in the cell is the alternative splicing of pre-mRNA. The authors present the results of scientific studies that show that pre-mRNA of more than 90 % of human genes are subjected to alternative splicing. It is presented that splicing is performed by a specialized macromolecular formation — suprasplicesome, which is a megacomplex (21 MDA) of nuclear ribonucleroprotein. It is shown that scientists have proposed two models of epigenetic regulation of splicing: kinetic and recruitment one. The authors reveal the main provisions of these models. MicroRNAs are actively involved in splicing. Liver disease may be based on a deficiency of splicing factors and deregulation of alternative splicing caused by the action of miRNAs. Disorders of alternative splicing, which stimulate proliferation, prevent apoptosis and support cell transformation, are a pathognomonic phenomenon in malignant tumors. Thus, the constituent mechanisms of action of intranuclear miRNAs are alteration of the ncRNAs transcriptome and participation in the regulation of alternative splicing. MicroRNA-mediated regulation of the stability of long ncRNAs causes a change in the spectrum of activity of expression of epigenetically regulated genes. Long ncRNAs are actively involved in the development of some liver diseases. Alternative splicing is an integral part of cell differentiation and contributes to the formation of tissue specificity. Alternative splicing and generation of various isoforms of proteins determine molecular consequences that cause the development of various pathological conditions.
... However, most studies of iMSCs have focused on the analysis of gene expression at the transcriptional level, whereas gene expression at the post-transcriptional level is much less clear. Post-transcriptional alternative splicing (AS) of precursor mRNAs, a major gene regulatory mechanism contributing to RNA and protein diversity, modulates almost all fundamental biological processes including tissue development and identity [22][23][24], as well as stem cell identity and stemness [25][26][27]. The regulatory roles of AS in MSCs that govern MSC identity, differentiation, and aging have been demonstrated [28][29][30][31][32]. ...
Although comparative genome-wide transcriptomic analysis has provided insight into the biology of human induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs), the distinct alternative splicing (AS) signatures of iMSCs remain elusive. Here, we performed Illumina RNA sequencing analysis to characterize AS events in iMSCs compared with tissue-derived MSCs. A total of 4586 differentially expressed genes (|FC| > 2) were identified between iMSCs and umbilical cord blood-derived MSCs (UCB-MSCs), including 2169 upregulated and 2417 downregulated genes. Of these, 164 differentially spliced events (BF > 20) in 112 genes were identified between iMSCs and UCB-MSCs. The predominant type of AS found in iMSCs was skipped exons (43.3%), followed by retained introns (19.5%), alternative 3′ (15.2%) and 5′ (12.8%) splice sites, and mutually exclusive exons (9.1%). Functional enrichment analysis showed that the differentially spliced genes (|FC| > 2 and BF > 20) were mainly enriched in functions associated with focal adhesion, extracellular exosomes, extracellular matrix organization, cell adhesion, and actin binding. Splice isoforms of selected genes including TRPT1, CNN2, and AP1G2, identified in sashimi plots, were further validated by RT-PCR analysis. This study provides valuable insight into the biology of iMSCs and the translation of mechanistic understanding of iMSCs into therapeutic applications.
... In addition to the transcriptional regulation of hypoxiatargeted genes, post-transcriptional processes, such as pre-mRNA alternative splicing (AS), were induced by hypoxia. AS is essential for gene expression regulation in higher eukaryotes [17,18]. It has been estimated that ~95% of human multi-exon genes undergo AS [19], and such AS events are particularly widespread in the central nervous system (CNS). ...
Exposure to specific doses of hypoxia can trigger endogenous neuroprotective and neuroplastic mechanisms of the central nervous system. These molecular mechanisms, together referred to as hypoxic preconditioning (HPC), remain poorly understood. In the present study, we applied RNA sequencing and bioinformatics analyses to study HPC in a whole-body HPC mouse model. The preconditioned (H4) and control (H0) groups showed 605 differentially expressed genes (DEGs), of which 263 were upregulated and 342 were downregulated. Gene Ontology enrichment analysis indicated that these DEGs were enriched in several biological processes, including metabolic stress and angiogenesis. The Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that the FOXO and Notch signaling pathways were involved in hypoxic tolerance and protection during HPC. Furthermore, 117 differential alternative splicing events (DASEs) were identified, with exon skipping being the dominant one (48.51%). Repeated exposure to systemic hypoxia promoted skipping of exon 7 in Edrf1 and exon 9 or 13 in Lrrc45. This study expands the understanding of the endogenous protective mechanisms of HPC and the DASEs that occur during HPC.
... A number of RNA binding proteins are dynamically regulated during reprogramming, suggesting an important role in mESC self-renewal (33). Previous studies have demonstrated that specific alternative splicing events can modulate transcriptional networks involved in pluripotency maintenance vs. differentiation (34,35). These results suggest that the differentially phosphorylated proteins identified in the present study reflect mESC cellular functions. ...
Leukemia inhibitory factor (LIF) is a stem cell growth factor that maintains self‑renewal of mouse embryonic stem cells (mESCs). LIF is a cytokine in the interleukin‑6 family and signals via the common receptor subunit gp130 and ligand‑specific LIF receptor. LIF causes heterodimerization of the LIF receptor and gp130, activating the Janus kinase/STAT and MAPK pathways, resulting in changes in protein phosphorylation. The present study profiled LIF‑mediated protein phosphorylation changes in mESCs via proteomic analysis. mESCs treated in the presence or absence of LIF were analyzed via two‑dimensional differential in‑gel electrophoresis and protein and phosphoprotein staining. Protein identification was performed by matrix‑assisted laser desorption/ionization‑time of flight mass spectrophotometry. Increased phosphorylation of 16 proteins and decreased phosphorylation of 34 proteins in response to LIF treatment was detected. Gene Ontology terms enriched in these proteins included 'organonitrogen compound metabolic process', 'regulation of mRNA splicing via spliceosome' and 'nucleotide metabolic process'. The present results revealed that LIF modulated phosphorylation levels of nucleotide metabolism‑associated proteins, thus providing insight into the mechanism underlying LIF action in mESCs.
