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Alternate exon switching establishes a tissue-specific transcription factor to mediate temporal activation of gene expression during differentiation

ABSTRACT: Although splicing occurs in most multi-exon genes, the generation of distinct isoforms through the alternate use of mutually exclusive exons is less prevalent. As exon-switching events have the potential to give rise to isoforms with different cellular functions, we have explored the role of the muscle-specific (Mef2Da2) and ubiquitously expressed (Mef2Da1) isoforms of the transcription factor Mef2D in myogenesis. Here we show that both isoforms of Mef2D bind a largely overlapping subset of genomic loci, yet only the muscle-specific Mef2Da2 isoform can activate the late myogenic gene expression program. This differential ability to activate transcription is modulated by PKA signaling where Mef2Da1 is efficiently phosphorylated by the kinase to enhance its association with repressive HDAC-deacetylase complexes. In contrast, alternate exon usage in Mef2Da2 renders the protein resistant to PKA phosphorylation, allowing it to interact with transcriptionally permissive Ash2L-trithorax complex. Our findings support a model wherein alternative exon usage allows Mef2D to transition from a repressor to activator in a myogenic environment rich in PKA activity. Thus we have identified a novel paradigm in which a ubiquitously expressed transcription factor has evolved to undergo tissue-specific alternative exon usage to permit the proper temporal activation of a gene expression program during differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE43223 | GEO | 2013/06/01

SECONDARY ACCESSION(S): PRJNA185319

REPOSITORIES: GEO

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Alternate exon switching establishes a tissue-specific transcription factor to mediate temporal activation of gene expression during differentiation

Project description:Although splicing occurs in most multi-exon genes, the generation of distinct isoforms through the alternate use of mutually exclusive exons is less prevalent. As exon-switching events have the potential to give rise to isoforms with different cellular functions, we have explored the role of the muscle-specific (Mef2Da2) and ubiquitously expressed (Mef2Da1) isoforms of the transcription factor Mef2D in myogenesis. Here we show that both isoforms of Mef2D bind a largely overlapping subset of genomic loci, yet only the muscle-specific Mef2Da2 isoform can activate the late myogenic gene expression program. This differential ability to activate transcription is modulated by PKA signaling where Mef2Da1 is efficiently phosphorylated by the kinase to enhance its association with repressive HDAC-deacetylase complexes. In contrast, alternate exon usage in Mef2Da2 renders the protein resistant to PKA phosphorylation, allowing it to interact with transcriptionally permissive Ash2L-trithorax complex. Our findings support a model wherein alternative exon usage allows Mef2D to transition from a repressor to activator in a myogenic environment rich in PKA activity. Thus we have identified a novel paradigm in which a ubiquitously expressed transcription factor has evolved to undergo tissue-specific alternative exon usage to permit the proper temporal activation of a gene expression program during differentiation. ChIP-Seq profiling of Mef2Da1 and Mef2Da2 isoforms generated by alternate splicing

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RNA-Seq profiling of C2C12 cells with exogenous expression of Mef2Da1 and Mef2Da2

Project description:Although splicing occurs in most multi-exon genes, the generation of distinct isoforms through the alternate use of mutually exclusive exons is less prevalent. As exon-switching events have the potential to give rise to isoforms with different cellular functions, we have explored the role of the muscle-specific (Mef2Da2) and ubiquitously expressed (Mef2Da1) isoforms of the transcription factor Mef2D in myogenesis. Here we show that both isoforms of Mef2D bind a largely overlapping subset of genomic loci, yet only the muscle-specific Mef2Da2 isoform can activate the late myogenic gene expression program. This differential ability to activate transcription is modulated by PKA signaling where Mef2Da1 is efficiently phosphorylated by the kinase to enhance its association with repressive HDAC-deacetylase complexes. In contrast, alternate exon usage in Mef2Da2 renders the protein resistant to PKA phosphorylation, allowing it to interact with transcriptionally permissive Ash2L-trithorax complex. Our findings support a model wherein alternative exon usage allows Mef2D to transition from a repressor to activator in a myogenic environment rich in PKA activity. Thus we have identified a novel paradigm in which a ubiquitously expressed transcription factor has evolved to undergo tissue-specific alternative exon usage to permit the proper temporal activation of a gene expression program during differentiation. RNA-Seq profiling of C2C12 cells with exogenous expression of Mef2Da1 and Mef2Da2

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RNA-Seq profiling of C2C12 cells with exogenous expression of Mef2Da1 and Mef2Da2

2013-06-03 | GSE46363 | GEO

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Neuronal activity regulates alternative exon usage

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Project description:We have performed a genome-wide analysis of common genetic variation controlling differential expression of transcript isoforms in the CEU HapMap population using a comprehensive exon tiling microarray covering 17,897 genes. We detected 324 genes with significant associations between flanking SNPs and transcript levels. Of these, 39% reflected changes in whole gene expression and 55% reflected transcript isoform changes such as splicing variants (exon skipping, alternate splice site usage, intron retention), differential 5’ UTR (initiation of transcription) usage, and differential 3’ UTR (alternative polyadenylation) usage. These results demonstrate that the regulatory effects of genetic variation in a normal human population are drastically more complex than previously observed. This additional layer of molecular diversity may account for natural phenotypic variation and disease susceptibility. Keywords: Comparative genomic hybridiation within the CEU HapMap population

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The dynamic landscape of fission yeast meiosis alternative-splice isoforms

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2016-11-10 | GSE79802 | GEO

Single-cell mRNA isoform diversity in the mouse brain

Project description:Single-cell isoform regulation is increasingly being studied. To get a full view of alternative isoform usage, from transcription start site and alternative splicing to transcription termination site, full-length sequences have to be studied. Here we use PacBio long read sequencing technology combined with unique molecular identities to get a full and accurate picture of alternative isoform usage of different stages in maturing oligodendrocyte single cells. We see that the majority of molecules in single-cells are separate isoforms, even after applying a conservative definition of what constitutes an isoform. Few isoforms are common between cells of the same cell-type but the common isoforms are higher expressed. We also see that exon junctions in coding regions are better regulated than exon junctions in non-coding regions and that genes often express more than one coding isoform.

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microRNA-222 regulates muscle alternative splicing through Rbm24 during differentiation of skeletal muscle cells

Project description:A number of microRNAs have been shown to regulate skeletal muscle development and differentiation. MicroRNA-222 is downregulated during myogenic differentiation and its overexpression leads to alteration of muscle differentiation process and specialized structures. By using RNA induced silencing complex (RISC) pulldown followed by RNA sequencing, combined with in silico microRNA target prediction, we have identified two new targets of microRNA-222 involved in the regulation of myogenic differentiation, Ahnak and Rbm24. Specifically, the RNA binding protein Rbm24 is a major regulator of muscle specific alternative splicing and its downregulation by microRNA-222 results in defective exon inclusion impairing the production of muscle-specific isoforms of Coro6, Fxr1 and NACA transcripts. Reconstitution of normal levels of Rbm24 in cells overexpressing microRNA-222 rescues muscle-specific splicing. In conclusion, we have identified a new function of microRNA-222 leading to alteration of myogenic differentiation at the level of alternative splicing, and we provide evidence that this effect is mediated by Rbm24 protein. We built linear models using 2 different experiments and two conditions (miR222 over expression (n=1) and control siRNA(n=2)) with the linear formula (~condition + experiment).

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