By regulating the timing of cellular processes, the circadian clock provides a
way to adapt physiology and behaviour to the geophysical time. In mammals, a
light-entrainable master clock located in the suprachiasmatic nucleus (SCN)
controls peripheral clocks that are present in virtually every body cell.
Defective circadian timing is associated with several pathologies such as
cancer and metabolic and sleep disorders. To better understand the circadian
regulation of cellular processes, we developed a bioinformatics pipeline
encompassing the analysis of high-throughput data sets and the exploitation of
published knowledge by text-mining. We identified 118 novel potential clock-
regulated genes and integrated them into an existing high-quality circadian
network, generating the to-date most comprehensive network of circadian
regulated genes (NCRG). To validate particular elements in our network, we
assessed publicly available ChIP-seq data for BMAL1, REV-ERBα/β and RORα/γ
proteins and found strong evidence for circadian regulation of Elavl1, Nme1,
Dhx6, Med1 and Rbbp7 all of which are involved in the regulation of
tumourigenesis. Furthermore, we identified Ncl and Ddx6, as targets of RORγ
and REV-ERBα, β, respectively. Most interestingly, these genes were also
reported to be involved in miRNA regulation; in particular, NCL regulates
several miRNAs, all involved in cancer aggressiveness. Thus, NCL represents a
novel potential link via which the circadian clock, and specifically RORγ,
regulates the expression of miRNAs, with particular consequences in breast
cancer progression. Our findings bring us one step forward towards a
mechanistic understanding of mammalian circadian regulation, and provide
further evidence of the influence of circadian deregulation in cancer
