Ontology highlight
ABSTRACT:
PROVIDER: PRJNA737012 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14793087_1.fastq.gz | Fastqsanger.gz | |||
| SRR14793087_2.fastq.gz | Fastqsanger.gz | |||
| SRR14793088_1.fastq.gz | Fastqsanger.gz | |||
| SRR14793088_2.fastq.gz | Fastqsanger.gz | |||
| SRR14793089_1.fastq.gz | Fastqsanger.gz |
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Project description:Genome-wide association studies (GWASs) have reported numerous genetic variations associated with schizophrenia, but knowledge regarding relevant molecular mechanisms is limited. Many genes undergo sophisticated alternative splicing in the brain, and aberrations of this process may contribute to the pathogenesis of schizophrenia. To examine modulated alternative splicing by genetic risk variant of schizophrenia, we performed genome-wide screening to identify schizophrenia risk single nucleotide polymorphisms that were associated with mRNA expression of alternative splicing junctions, especially previously unannotated junctions. Among the 14,465 schizophrenia risk SNPs, 17,107 splicing QTLs (sQTLs) for previously unannotated splicing junctions were identified in two independent brain RNA-Seq datasets (BrainSeq and CommonMind Consortium). Functional predictions using the deep neural network SpliceAI found 7 likely causal risk SNPs, among which a synonymous SNP rs3935873 in DOC2A at 16p11.2 GWAS locus showed the highest score and was significantly associated with elevated mRNA expression of a previously uncharacterized alternatively spliced DOC2AMutant isoform. In vitro minigene assays confirmed the selective regulatory effect of rs3935873 on the expression of DOC2AMutant rather than the wild-type DOC2AFull, suggesting its putatively causal role in the splicing of DOC2A. The SNP rs3935873 was significantly associated with hippocampal volume, and overexpressing DOC2AMutant in the hippocampus lead to multiple schizophrenia-like behavioral phenotypes, including aberrant prepulse inhibition (PPI), which are distinct from the mice overexpressing DOC2AFull. Both DOC2AMutant and DOC2AFull overexpression led to increased number of synapses, whereas DOC2AMutant reduced synaptic vesicle densities and postsynaptic density (PSD) width. Mechanistically, DOC2AMutant had distinct three-dimensional structure compared with DOC2AFull, and specifically-bound proteins were involved in the “regulation of actin cytoskeleton” and “Hippo signaling pathways”. Taken together, this study provides a splicing mechanism for the prominent 16p11.2 locus schizophrenia association, suggesting that sQTL analyses with previously uncharacterized isoforms could provide novel insights into the molecular mechanisms underlying GWAS associations.
2025-02-12 | PXD060711 |
Project description:The investigation of spliceosomal processes is currently a topic of intense research in molecular biology. In the molecular mechanism of alternative splicing, a multi-protein–RNA complex – the spliceosome – plays a crucial role. To understand the biological processes of alternative splicing, it is essential to comprehend the biogenesis of the spliceosome.
In this paper, we propose the first abstract model of the regulatory assembly pathway of the human spliceosomal subunit U1. Using Petri nets, we describe its highly ordered assembly that takes place in a stepwise manner.
2024-10-31 | MODEL2410300001 | BioModels
Project description:The Cell Division Cycle and Apoptosis Regulator (CCAR) protein family members have recently emerged as regulators of alternative splicing and transcription, as well as having other key physiological functions. For example, mammalian CCAR2/DBC1 forms a complex with the zinc factor protein ZNF326 to integrate alternative splicing with RNA polymerase II transcriptional elongation in AT-rich regions of the DNA. Additionally, Caenorhabditis elegans CCAR-1, a homolog to mammalian CCAR2, facilitates the alternative splicing of the perlecan unc-52 gene. However, much about the CCAR family's role in alternative splicing is unknown. We are interested in uncovering the role of the CCAR family in alternative splicing in vivo using Caenorhabditis elegans. We examined the role of CCAR-1 in genome-wide alternative splicing and identified new alternative splicing targets of CCAR-1 using RNA sequencing. Also, we found that CCAR-1 interacts with the spliceosome factors UAF-1 and UAF-2 using mass spectrometry, and that knockdown of ccar-1 affects alternative splicing patterns, motility, and proteostasis of UAF-1 mutant worms. Collectively, we demonstrate a role for CCAR-1 in the regulation of global alternative splicing in C. elegans and in conjunction with UAF-1
2024-02-26 | PXD043100 | Pride
Project description:This SuperSeries is composed of the following subset Series: GSE34992: Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins (splice array) GSE34993: Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins (CLIP-Seq) GSE34995: Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins (RNA-Seq) Refer to individual Series
2012-02-20 | E-GEOD-34996 | biostudies-arrayexpress
Project description:Genome-wide analysis of alternative splicing in Zea mays: landscape and genetic regulation
2020-04-14 | E-GEOD-57337 | ExpressionAtlas
Project description:Alternative splicing (AS) is an important component of RNA processing controlled by cis- and trans-acting component. Here we investigate modes and mechanisms of AS co-regulation by MBNL1 and RBFOX1. We generated two cell models (human and mouse) whereby the expression of both RBPs can be independently modulated and utilize these cell lines to perform RNAseq and transcriptome wide alternative splicing analysis. Categorization of alternative splicing outcomes of the impacts of RBFOX1 expression on MBNL1 splicing revealed a common co-regulatory mode whereby RBFOX1 buffers MBNL1 dose-dependent splicing regulation by reducing the total range of exon inclusion induced. Overall, our studies define a conserved co-regulatory mechanism through which RBFOX1 and MBNL1 can fine-tune and provide redundancy for AS outcomes.
2021-03-25 | GSE169518 | GEO
Project description:Alternative splicing is a crucial mechanism for gene regulation that is modulated in response to a wide range of extracellular stimuli. Stress-activated protein kinases (SAPKs) play a key role in controlling several steps of mRNA biogenesis. Here, we show that osmostress has a major impact on the regulation of alternative splicing (AS), which is partly mediated through the action of the p38 SAPK. Remarkably, a splicing network analysis revealed a functional connection between p38 and the spliceosome component SKIIP. Depletion of SKIIP abolished a significant part of the p38-mediated alternative splicing.
2019-04-16 | GSE117699 | GEO
Project description:Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
2024-04-25 | PXD050320 | Pride
Project description:Epithelial specific splicing regulatory protein 1 and 2 (ESRP1 and ESRP2) are important regulators of alternative splicing during EMT. To study the alternative splicing events regulated by ESRP1/2 at a genome wide scale, we used lentiviral shRNAs to knockdown ESRP1/2 in H358 cells and performed RNA-seq in biological triplicates.
2016-04-05 | GSE75489 | GEO