Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver

Tung T. Nguyen, John S.A. Mattick, Qian Yang, Mehmet A. Orman, Marianthi G. Ierapetritou, Francois Berthiaume, Ioannis P. Androulakis

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Background: The circadian clock is a critical regulator of biological functions controlling behavioral, physiological and biochemical processes. Because the liver is the primary regulator of metabolites within the mammalian body and the disruption of circadian rhythms in liver is associated with severe illness, circadian regulators would play a strong role in maintaining liver function. However, the regulatory structure that governs circadian dynamics within the liver at a transcriptional level remains unknown. To explore this aspect, we analyzed hepatic transcriptional dynamics in Sprague-Dawley rats over a period of 24 hours to assess the genome-wide responses.Results: Using an unsupervised consensus clustering method, we identified four major gene expression clusters, corresponding to central carbon and nitrogen metabolism, membrane integrity, immune function, and DNA repair, all of which have dynamics which suggest regulation in a circadian manner. With the assumption that transcription factors (TFs) that are differentially expressed and contain CLOCK:BMAL1 binding sites on their proximal promoters are likely to be clock-controlled TFs, we were able to use promoter analysis to putatively identify additional clock-controlled TFs besides PARF and RORA families. These TFs are both functionally and temporally related to the clusters they regulate. Furthermore, we also identified significant sets of clock TFs that are potentially transcriptional regulators of gene clusters.Conclusions: All together, we were able to propose a regulatory structure for circadian regulation which represents alternative paths for circadian control of different functions within the liver. Our prediction has been affirmed by functional and temporal analyses which are able to extend for similar studies.

Original languageEnglish (US)
Article number83
JournalBMC Bioinformatics
Issue number1
StatePublished - Mar 25 2014

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics


  • Circadian regulation
  • Circadian rhythm
  • Consensus clustering
  • Gene expression
  • Microarray analysis
  • Promoter analysis
  • Transcription factor


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