title: Bioinformatics analysis of transcriptional regulation of circadian genes in rat liver.
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.
authors.forename: Tung T
authors.initials: TT
authors.lastname: Nguyen
authors.forename: John S A
authors.initials: JS
authors.lastname: Mattick
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.forename: Mehmet A
authors.initials: MA
authors.lastname: Orman
authors.forename: Marianthi G
authors.initials: MG
authors.lastname: Ierapetritou
authors.forename: Francois
authors.initials: F
authors.lastname: Berthiaume
authors.affiliation: Chemical and Biochemical Engineering Department, Rutgers the State University of New Jersey, Piscataway, NJ 08854, USA. yannis@rci.rutgers.edu.
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Androulakis
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics*; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D056925:Circadian Rhythm Signaling Peptides and Proteins; D014157:Transcription Factors