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

1
Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, and Berlin Institute of Health, Institute for Theoretical Biology, 10115 Berlin, Germany
2
Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt—Universität zu Berlin, and Berlin Institute of Health, Medical Department of Hematology, Oncology, and Tumor Immunology, Molecular Cancer Research Center, 13353 Berlin, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(5), 1182; https://doi.org/10.3390/ijms20051182
Received: 15 February 2019 / Revised: 1 March 2019 / Accepted: 5 March 2019 / Published: 8 March 2019
(This article belongs to the Special Issue Tumor Necrosis Factor (TNF))
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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. View Full-Text
Keywords: circadian clock; cancer; systems biology; high-throughput data analysis; alternative splicing; analysis of oscillating genes; pathway enrichment; RNA-sequencing; TNF-pathway circadian clock; cancer; systems biology; high-throughput data analysis; alternative splicing; analysis of oscillating genes; pathway enrichment; RNA-sequencing; TNF-pathway
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Genov, N.; Basti, A.; Abreu, M.; Relógio, A. Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines. Int. J. Mol. Sci. 2019, 20, 1182.

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