Abstract
The circadian clock regulates key cellular processes and its dysregulation is associated to several pathologies including cancer. Although the transcriptional regulation of gene expression by the clock machinery is well described, the role of the clock in the regulation of post-transcriptional processes, including splicing, remains poorly understood. In the present work, we investigated the putative interplay between the circadian clock and splicing in a cancer context. For this, we applied a computational pipeline to identify oscillating genes and alternatively spliced transcripts in time-course high-throughput data sets from normal cells and tissues, and cancer cell lines. We investigated the temporal phenotype of clock-controlled genes and splicing factors, and evaluated their impact in alternative splice patterns in the Hodgkin Lymphoma cell line HD-MY-Z. Our data points to a connection between clock-controlled genes and splicing factors, which correlates with temporal alternative splicing in several genes in the HD-MY-Z cell line. These include the genes DPYD, SS18, VIPR1 and IRF4, involved in metabolism, cell cycle, apoptosis and proliferation. Our results highlight a role for the clock as a temporal regulator of alternative splicing, which may impact malignancy in this cellular model.
Highlights
Pre-mRNA splicing is a fundamental biological process through which the introns of a nascent RNA are removed and exons are merged to form a mature RNA that is translated into a protein
Cluster 8 shows a strong correlation to RNA Polymerase II (p = 1.018E-19) and nonsense-mediated decay (NMD) appears enriched for two of the clusters (Cluster 9 and 3, p = 1.626E11 and 2.371E-02 respectively), a process which is involved in the degradation of aberrant mRNA isoforms
We explored the role of the circadian clock network in influencing alternative splicing in HD-MY-Z cells with a bioinformatics approach using time-course microarray data recently published by our group[27]
Summary
Pre-mRNA splicing is a fundamental biological process through which the introns of a nascent RNA are removed and exons are merged to form a mature RNA that is translated into a protein. We used a recently published[31] time-course data set for the HD-MY-Z cell line, for which stage-specific patterns of AS have previously been described[11], as a cellular model system to investigate a possible correlation between the circadian clock and the splicing machinery. We analysed the extent of AS events in the HD-MY-Z cell line in a time-dependant manner and identified several genes, including DPYD (dihydropyrimidine dehydrogenase), IRF4 (interferon regulatory factor 4), POP4 (POP4 homolog, ribonuclease P/MRP subunit), SS18 (nBAF chromatin remodelling complex subunit), MAGOH (mago homolog, exon junction complex subunit) and VIPR1 (vasoactive intestinal peptide receptor 1), involved in the cell cycle, apoptosis, drug metabolism and RNA processing and splicing that show expression patterns resulting from a temporal AS. Our results emphasize the existence of a putative circadian regulation of SF that subsequently may impact on AS decisions potentially relevant in cancer onset and or progression
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