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Open Access Highly Accessed Research article

Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver

Tung T Nguyen2, John SA Mattick1, Qian Yang1, Mehmet A Orman1, Marianthi G Ierapetritou1, Francois Berthiaume3 and Ioannis P Androulakis13*

Author Affiliations

1 Chemical and Biochemical Engineering Department, Rutgers the State University of New Jersey, Piscataway, NJ 08854, USA

2 BioMaPS Institute for Quantitative Biology, Rutgers the State University of New Jersey, Piscataway, NJ 08854, USA

3 Biomedical Engineering Department, Rutgers the State University of New Jersey, Piscataway, NJ 08854, USA

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BMC Bioinformatics 2014, 15:83  doi:10.1186/1471-2105-15-83

Published: 25 March 2014

Abstract

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.

Keywords:
Circadian rhythm; Microarray analysis; Gene expression; Consensus clustering; Promoter analysis; Transcription factor; Circadian regulation