Structural evolution of the tissue-specific U2AF paralog and alternative splicing factor LS2
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE156213 | GEO | 2023/08/01
REPOSITORIES: GEO
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Project description:Structural evolution of the tissue-specific U2AF paralog and alternative splicing factor LS2
| PRJNA657056 | ENA
Project description:Alternative splicing is a rich source of tumor-specific neoantigen targets for immunotherapy. This holds promise for glioblastomas (GBMs), the most common primary tumors of the adult brain, which are resistant to standard-of-care therapy. Although most clinical trials enroll patients at recurrence, most preclinical studies have been done with specimens from primary disease. There are limited expression data from GBMs at recurrence and surprisingly little is known about the evolution of splicing patterns under therapy. We profiled 29 primary-recurrent paired human GBM specimens via RNA sequencing. We describe the landscape of alternative splicing in GBM at recurrence and contrast that to primary and non-malignant brain-tissue specimens. By screening single-cell atlases, we identify cell-type specific splicing patterns and novel splicing events in cell-surface proteins that are suitable targets for engineered T-cell therapies. We identify recurrent-specific isoforms of mitogen-activated kinase pathway genes that enhance invasiveness and are preferentially expressed by stem-like cells. These studies shed light on gene expression in recurrent GBM and identify novel targets for therapeutic development.
2020-12-10 | GSE155434 | GEO
Project description:Thousands of human genes contain introns ending in NAGNAG motifs (N any nucleotide), where both NAGs can function as 3' splice sites, yielding isoforms differing by inclusion/exclusion of just three bases. However, the functional importance of NAGNAG alternative splicing is highly controversial. Using very deep RNA-Seq data from sixteen human and eight mouse tissues, we found that approximately half of alternatively spliced NAGNAGs undergo tissue-specific regulation and that regulated events have been selectively retained: alternative splicing of strongly tissue-specific NAGNAGs was ten times as likely to be conserved between species as for non-tissue-specific events. Further, alternative splicing of human NAGNAGs was associated with an order of magnitude increase in the frequency of exon length changes at orthologous mouse/rat exon boundaries, suggesting that NAGNAGs accelerate exon evolution. Together, our analyses show that NAGNAG alternative splicing constitutes a major generator of tissue-specific proteome diversity and accelerates evolution of proteins at exon-exon boundaries. mRNA-Seq of sixteen human and eight mouse tissues. Supplementary files: human.nagnag.junctions.gff and mouse.nagnag.junctions.gff are the annotation files (in GFF3 format) corresponding to the 'bwtout' mapped reads files linked to the Sample records. Raw data files provided for Samples GSM742937-GSM742952 only.
2012-01-05 | E-GEOD-30017 | biostudies-arrayexpress
Project description:Regulation and functionality of species-specific alternative splicing has remained enigmatic for many years. Calcium/calmodulin-dependent protein kinase IIβ (CaMKIIβ) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specific CAMK2B splice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specific Camk2β alternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strength during evolution globally renders constitutive exons alternative, thus providing a paradigm for cis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9 we introduced the weaker human branch point into the mouse genome, resulting in human-like CAMK2B splicing in the brain of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point-controlled, species-specific alternative splicing with a fundamental function in learning and memory.
2022-12-19 | PXD035346 | Pride
Project description:Thousands of human genes contain introns ending in NAGNAG motifs (N any nucleotide), where both NAGs can function as 3' splice sites, yielding isoforms differing by inclusion/exclusion of just three bases. However, the functional importance of NAGNAG alternative splicing is highly controversial. Using very deep RNA-Seq data from sixteen human and eight mouse tissues, we found that approximately half of alternatively spliced NAGNAGs undergo tissue-specific regulation and that regulated events have been selectively retained: alternative splicing of strongly tissue-specific NAGNAGs was ten times as likely to be conserved between species as for non-tissue-specific events. Further, alternative splicing of human NAGNAGs was associated with an order of magnitude increase in the frequency of exon length changes at orthologous mouse/rat exon boundaries, suggesting that NAGNAGs accelerate exon evolution. Together, our analyses show that NAGNAG alternative splicing constitutes a major generator of tissue-specific proteome diversity and accelerates evolution of proteins at exon-exon boundaries.
2012-01-05 | GSE30017 | GEO
Project description:We studied the evolution of alternative splicing in the early stages of species divergence in the house mouse. We sequenced the testis transcriptomes of three Mus musculus subspecies and Mus spretus using Illumina technology. On the basis of a genome-wide analysis of read coverage differences among subspecies, we identified several hundred candidate alternatively spliced regions.
2010-02-28 | E-GEOD-18905 | biostudies-arrayexpress
Project description:Assessing the influence of RNA structural and sequence variations on SNRPA1-mediated regulation of alternative splicing
2021-03-30 | GSE160955 | GEO
Project description:We studied the evolution of alternative splicing in the early stages of species divergence in the house mouse.
2010-02-28 | GSE18905 | GEO
Project description:CLAMP is a GA-repeat motif binding transcription factor that regulates gene expression. We hypothesized that CLAMP also regulates RNA processing, specifically alternative splicing that occurs co-transcriptionally because CLAMP is bound to intronic regions that are rich in polypyrimidine tracts which contain GA-rich sequences. Furthermore, GA-rich repeat sequences are thought to have evolved from polypyrimidine tracts that regulate splicing. Also, MALDI-mass spectrometry data identifying putative CLAMP interactors found association with 33 RNA binding proteins, including 6 that regulate alternative splicing. Thus, to test our hypothesis that CLAMP shapes transcriptome diversity by regulating RNA transcript splicing, we performed mRNA-sequencing in the presence and absence of CLAMP in Kc (female) and S2 (male) cell lines and used a SUPPA based pipeline called time2splice (https://github.com/ashleymaeconard/time2splice) to analyze the sequencing data. Using both cell lines helped us to identify female (Kc) and male (S2) specific splicing events. We identified 452 genes differentially spliced beetween Kc and S2 cells. There are 46 and 113 CLAMP-dependent splicing events in Kc and S2 cells, respectively. Interestingly, 45 CLAMP-dependent events (belonging to 42 genes) are specific to Kc cells, i.e female-specific, whereas 112 CLAMP dependent events (belonging to 100 genes) in S2 cells are specific to S2 cells, i.e male-specific. Therefore, we identified a new role for the transcription factor CLAMP in regulated sex-specific splicing events in Kc and S2 cells.
2023-08-02 | GSE220439 | GEO
Project description:BACKGROUND:The CEA gene family is one of the most rapidly evolving gene families in the human genome. The founder gene of the family is thought to be an ancestor of the inhibitory immune checkpoint molecule CEACAM1. Comprehensive analyses of mammalian genomes showed that the CEA gene family is subject to tremendous gene family expansion and contraction events in different mammalian species. While in some species (e.g. rabbits) less than three CEACAM1 related genes exist, were in others (certain microbat species) up to 100 CEACAM1 paralogs identified. We have recently reported that the horse has also an extended CEA gene family. Since mechanisms of gene family expansion and diversification are not well understood we aimed to analyze the equine CEA gene family in detail. RESULTS:We found that the equine CEA gene family contains 17 functional CEACAM1-related genes. Nine of them were secreted molecules and eight CEACAMs contain transmembrane and cytoplasmic domain exons, the latter being in the focus of the present report. Only one (CEACAM41) gene has exons coding for activating signaling motifs all other CEACAM1 paralogs contain cytoplasmic exons similar to that of the inhibitory receptor CEACAM1. However, cloning of cDNAs showed that only one CEACAM1 paralog contain functional immunoreceptor tyrosine-based inhibitory motifs in its cytoplasmic tail. Three receptors have acquired a stop codon in the transmembrane domain and two have lost their inhibitory motifs due to alternative splicing events. In addition, alternative splicing eliminated the transmembrane exon sequence of the putative activating receptor, rendering it to a secreted molecule. Transfection of eukaryotic cells with FLAG-tagged alternatively spliced CEACAMs indicates that they can be expressed in vivo. Thus detection of CEACAM41 mRNA in activated PBMC suggests that CEACAM41 is secreted by lymphoid cells upon activation. CONCLUSIONS:The results of our study demonstrate that alternative splicing after gene duplication is a potent mechanism to accelerate functional diversification of the equine CEA gene family members. This potent mechanism has created novel CEACAM receptors with unique signaling capacities and secreted CEACAMs which potentially enables equine lymphoid cells to control distantly located immune cells.
| S-EPMC5856374 | biostudies-literature