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.
Highlights
Alternative splicing (AS) belongs to one of the key biological processes, which regulates gene expression diversity and function in eukaryotes
Previous research pointed at the relevance of splicing in cancer, and identified cell-specific AS changes in HL cell lines [4,13,29]
In order to investigate the time-distribution of the isoforms detected in haematological cell lines we used a B lymphoblastoid cell line LCL-HO, the Hodgkin lymphoma cell lines HD-MY-Z and L-1236 and generated a total of 33 time-course data sets, which were subsequently sequenced
Summary
Alternative splicing (AS) belongs to one of the key biological processes, which regulates gene expression diversity and function in eukaryotes. We generated 33 time-course data sets (sampling every three hours between ZT12 h and ZT42 h) to investigate the time-dependent production of isoforms in two HL cell lines at different stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on TNF pathway-related elements. We identified several genes involved in the TNF pathway to undergo a time-dependent change in isoform expression with potential implications on the output of the pathway These include TNF receptor-associated factor 1 (TRAF1), TNF receptor superfamily 12A (TNFRSF12A) and the nuclear factor kappa B subunit 2 (NFKB2) with relevant functions in cell proliferation, migration and apoptosis. Our results further emphasize the potential impact of AS in cellular physiology, in a cancer context, and highlight the effect of temporal isoform switching events as mediators of these processes
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