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Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines

ABSTRACT: Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present work, we investigated the time-dependent production of isoforms in two Hodgkin lymphoma cell lines of different progression stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on tumour necrosis factor (TNF) pathway-related elements. For this, we used newly generated time-course RNA-sequencing data from the mentioned cell lines and applied a computational pipeline to identify genes with isoform-switching behaviour in time. We analysed the temporal profiles of the identified events and evaluated in detail the potential functional implications of alterations in isoform expression for the selected top-switching genes. Our data indicate that elements within the TNF pathway undergo a time-dependent variation in isoform production with a putative impact on cell migration, proliferation and apoptosis. These include the genes TRAF1, TNFRSF12A and NFKB2. Our results point to a role of temporal alternative splicing in isoform production, which may alter the outcome of the TNF pathway and impact on tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE162602 | GEO | 2020/12/04

REPOSITORIES: GEO

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Alternative splicing is frequent during early embryonic development in mouse

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2010-07-30 | E-GEOD-21971 | biostudies-arrayexpress

Alternative splicing is frequent during early embryonic development in mouse

2010-06-29 | GSE21971 | GEO

Isoform switching events in esophageal adenocarcinoma progression

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2022-08-17 | GSE193946 | GEO

SRSF7-mediated Alternative Splicing of USO1 Promotes Hepatocellular Carcinoma by Activating the MAPK/ERK1-ELK1 Pathway

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Determining the impact of alternative splicing events on transcriptome dynamics

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2010-02-10 | E-GEOD-19373 | biostudies-arrayexpress

Differential transcript isoform usage pre- and post-zygotic genome activation in zebrafish

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2012-12-15 | E-GEOD-32932 | biostudies-arrayexpress

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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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