A Systems-Level Analysis Reveals Circadian Regulation of Splicing in Colorectal Cancer

EBioMedicine. 2018 Jul;33:68-81. doi: 10.1016/j.ebiom.2018.06.012. Epub 2018 Jun 21.


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: Alternative splicing; Circadian clock; Colorectal cancer progression; Differential rhythmicity; Spliceosome; Splicing factors.

MeSH terms

  • Alternative Splicing*
  • Cell Line, Tumor
  • Circadian Clocks*
  • Circadian Rhythm
  • Colorectal Neoplasms / genetics*
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genome-Wide Association Study
  • Humans
  • Neoplasm Metastasis
  • Oligonucleotide Array Sequence Analysis / methods*