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Global genetic robustness of the alternative splicing machinery in C. elegans

ABSTRACT: Alternative splicing is considered a major mechanism for creating multicellular diversity from a limited repertoire of genes. Different isoforms can be produced at the same time in the same cell type and their ratios can be the same or different between divergent genotypes. Here, we studied genetic variation in alternative splicing patterns in a large recombinant inbred population of C. elegans, using whole-genome tiling arrays. This experiment allowed us to detect heritable differences in gene expression with exquisite sensitivity and resolution, and we detected 435 genes with substantial heritable variation for at least one exon. Nonetheless, we find only a very small number of examples of heritable variation in alternative splicing (22 transcripts), and most of these genes co-localize with the associated genomic loci. This is in striking contrast to earlier observations in humans, which showed much less genetic robustness.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE15778 | GEO | 2011/01/01

SECONDARY ACCESSION(S): PRJNA116849

REPOSITORIES: GEO

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Global genetic robustness of the alternative splicing machinery in C. elegans

Project description:Alternative splicing is considered a major mechanism for creating multicellular diversity from a limited repertoire of genes. Different isoforms can be produced at the same time in the same cell type and their ratios can be the same or different between divergent genotypes. Here, we studied genetic variation in alternative splicing patterns in a large recombinant inbred population of C. elegans, using whole-genome tiling arrays. This experiment allowed us to detect heritable differences in gene expression with exquisite sensitivity and resolution, and we detected 435 genes with substantial heritable variation for at least one exon. Nonetheless, we find only a very small number of examples of heritable variation in alternative splicing (22 transcripts), and most of these genes co-localize with the associated genomic loci. This is in striking contrast to earlier observations in humans, which showed much less genetic robustness. C. elegans recombinant inbred lines were generated and genotyped as described in (Li et al. 2006). mRNA was isolated from 60 RILs reared under standard condition and hybridized to Affymetrix 1.0 C. elegans tiling arrays. The hybridization was done by ServiceXS (Leiden, The Netherlands).

2011-01-01 | E-GEOD-15778 | biostudies-arrayexpress

Regulation of alternative splicing by the core spliceosomal machinery

Project description:Abstract: Alternative splicing (AS) plays a major role in the generation of proteomic diversity and in gene regulation. However, the role of the basal splicing machinery in regulating AS remains poorly understood. Here we show that the core snRNP protein SmB/B’ self-regulates its expression by promoting the inclusion of a highly-conserved alternative exon in its own pre-mRNA that targets the spliced transcript for nonsense-mediated mRNA decay (NMD). Depletion of SmB/B’ in human cells results in reduced levels of snRNPs and in a striking reduction in the inclusion levels of hundreds of alternative exons, with comparatively few effects on constitutive exon splicing levels. The affected alternative exons are enriched in genes encoding RNA processing and other RNA binding factors, and a subset of these exons also regulate gene expression by activating NMD. Our results thus demonstrate a role for the core spliceosomal machinery in controlling an exon network that appears to modulate the levels of many RNA processing factors. HeLa cells were transfected with a control non-targeting siRNA pool (siNT), or with siRNA pools designed to knockdown SmB/B' or SRSF1 (also known as SF2/ASF/SFRS1). Sequence reads were aligned to exon-exon junction sequences in a database of EST/cDNA-mined cassette-type alternative splicing events. Processed data files (.bed and .txt) provided as supplementary files on the Series record. Processed data file build information: hg18.

2011-02-01 | E-GEOD-26463 | biostudies-arrayexpress

Sex and line specific gene expression and alternative splicing in Drosophila revealed

Project description:Many multi-exon genes are subject to alternative splicing, which is thought to increase phenotypic complexity by allowing a single locus to produce multiple functionally distinct proteins. However, genetic and developmental variation in alternative splicing has never been examined systematically. We therefore undertook a genome-wide analysis of sex- and genotypic-specific splicing in Drosophila in conjunction with sex- and line-specific transcription. Keywords: microarray, sexual dimorphism, alternative splicing, genetical genomics, genetic variation

2006-06-06 | GSE4976 | GEO

Regulation of alternative splicing by the core spliceosomal machinery

2011-02-01 | GSE26463 | GEO

Alternative Isoform Regulation in Human Tissue Transcriptomes

Project description:Through alternative processing of pre-mRNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes based on deep sequencing of cDNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analysis of mappings of sequence reads to exon-exon junctions indicated that ~94% of human genes undergo alternative splicing (AS), ~86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that a majority of AS and alternative cleavage and polyadenylation (APA) events exhibit variation between tissues. Variations in alternative mRNA isoform expression between 6 individuals were also detected in cerebellar cortex, with ~2- to 3-fold less isoform variation observed between individuals than between tissues. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation and with generation of full-length open reading frames. Patterns of AS and APA were strongly correlated across tissues, suggesting coordinated regulation, and sequence conservation of known regulatory motifs in both regulated introns and 3' UTRs suggested common involvement of the same factors in regulation of tissue-specific splicing and polyadenylation. Exam mRNA expression in 15 human tissues and cell lines

2008-09-30 | E-GEOD-12946 | biostudies-arrayexpress

Post-transational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_SI_24hr_300bp]

Project description:In this study, we show that pediatric T-cell acute lymphoblastic leukemia (T-ALL) has an alternative mechanism for aberrant splicing that involves post-translational regulation of the splicing machinery via deubiquitination.

2020-06-01 | GSE149624 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_shSRSF6]

2020-06-01 | GSE139621 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [CUTLL1_P5091]

2020-06-01 | GSE139620 | GEO

Post-translational regulation of the exon skipping machinery controls aberrant splicing in T cell leukemia [Jurkat_P5091]

2020-06-01 | GSE139619 | GEO

Tethering distinct molecular profiles of single cells by their lineage histories to investigate sources of cell state heterogeneity

Project description:Gene expression heterogeneity is ubiquitous within single cell datasets, even among cells of the same type. Heritable expression differences, defined here as those which persist over multiple cell divisions, are of particular interest, as they can underlie processes including cell differentiation during development as well as the clonal selection of drug-resistant cancer cells. However, heritable sources of variation are difficult to disentangle from non-heritable ones, such as cell cycle stage, asynchronous transcription, and measurement noise. Since heritable states should be shared by lineally related cells, we sought to leverage CRISPR-based lineage tracing, together with single cell molecular profiling, to discriminate between heritable and non-heritable variation in gene expression. We show that high efficiency capture of lineage profiles alongside single cell gene expression enables accurate lineage tree reconstruction and reveals an abundance of progressive, heritable gene expression changes. We find that a subset of these are likely mediated by structural genetic variation (copy number alterations, translocations), but that the stable attributes of others cannot be understood with expression data alone. Towards addressing this, we develop a method to capture cell lineage histories alongside single cell chromatin accessibility profiles, such that expression and chromatin accessibility of closely related cells can be linked via their lineage histories. We call this then leverage this indirect “coassay” approach "THE LORAX" and leverage it to explore the genetic and epigenetic mechanisms underlying heritable gene expression changes. Using this approach, we show that we can discern between heritable gene expression differences mediated by large and small copy number changes, trans effects, and possible epigenetic variation.

2022-05-12 | GSE201339 | GEO

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