A Systems-Level Analysis Reveals Circadian Regulation of Splicing in Colorectal Cancer
Rukeia El-Athman,
Luise Fuhr,
Angela Relógio
Affiliations
Rukeia El-Athman
Institute for Theoretical Biology (ITB), Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany; Medical Department of Hematology, Oncology, and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany
Luise Fuhr
Institute for Theoretical Biology (ITB), Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany; Medical Department of Hematology, Oncology, and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany
Angela Relógio
Institute for Theoretical Biology (ITB), Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany; Medical Department of Hematology, Oncology, and Tumor Immunology, Molekulares Krebsforschungszentrum (MKFZ), Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Germany; Corresponding author.
Accumulating evidence points to a significant role of the circadian clock in the regulation of splicing in various organisms, including mammals. Both dysregulated circadian rhythms and aberrant pre-mRNA splicing are frequently implicated in human disease, in particular in cancer. To investigate the role of the circadian clock in the regulation of splicing in a cancer progression context at the systems-level, we conducted a genome-wide analysis and compared the rhythmic transcriptional profiles of colon carcinoma cell lines SW480 and SW620, derived from primary and metastatic sites of the same patient, respectively. We identified spliceosome components and splicing factors with cell-specific circadian expression patterns including SRSF1, HNRNPLL, ESRP1, and RBM 8A, as well as altered alternative splicing events and circadian alternative splicing patterns of output genes (e.g., VEGFA, NCAM1, FGFR2, CD44) in our cellular model. Our data reveals a remarkable interplay between the circadian clock and pre-mRNA splicing with putative consequences in tumor progression and metastasis. Keywords: Circadian clock, Colorectal cancer progression, Spliceosome, Splicing factors, Alternative splicing, Differential rhythmicity
