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 Mar 8;20(5):1182. doi: 10.3390/ijms20051182.


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.

Keywords: RNA-sequencing; TNF-pathway; alternative splicing; analysis of oscillating genes; cancer; circadian clock; high-throughput data analysis; pathway enrichment; systems biology.

MeSH terms

  • Alternative Splicing*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Circadian Clocks
  • Hodgkin Disease / genetics*
  • Hodgkin Disease / metabolism
  • Hodgkin Disease / pathology
  • Humans
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA / genetics
  • Sequence Analysis, RNA
  • Signal Transduction*
  • Transcriptome*
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / metabolism


  • Protein Isoforms
  • Tumor Necrosis Factor-alpha
  • RNA