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Comparative Study
. 2008 Oct;4(10):e1000193.
doi: 10.1371/journal.pcbi.1000193. Epub 2008 Oct 10.

Analysis of gene regulatory networks in the mammalian circadian rhythm

Jun Yan  1 , Haifang Wang, Yuting Liu, Chunxuan Shao
Affiliations
Comparative Study

Analysis of gene regulatory networks in the mammalian circadian rhythm

Jun Yan et al. PLoS Comput Biol. 2008 Oct.

Abstract

Circadian rhythm is fundamental in regulating a wide range of cellular, metabolic, physiological, and behavioral activities in mammals. Although a small number of key circadian genes have been identified through extensive molecular and genetic studies in the past, the existence of other key circadian genes and how they drive the genomewide circadian oscillation of gene expression in different tissues still remains unknown. Here we try to address these questions by integrating all available circadian microarray data in mammals. We identified 41 common circadian genes that showed circadian oscillation in a wide range of mouse tissues with a remarkable consistency of circadian phases across tissues. Comparisons across mouse, rat, rhesus macaque, and human showed that the circadian phases of known key circadian genes were delayed for 4-5 hours in rat compared to mouse and 8-12 hours in macaque and human compared to mouse. A systematic gene regulatory network for the mouse circadian rhythm was constructed after incorporating promoter analysis and transcription factor knockout or mutant microarray data. We observed the significant association of cis-regulatory elements: EBOX, DBOX, RRE, and HSE with the different phases of circadian oscillating genes. The analysis of the network structure revealed the paths through which light, food, and heat can entrain the circadian clock and identified that NR3C1 and FKBP/HSP90 complexes are central to the control of circadian genes through diverse environmental signals. Our study improves our understanding of the structure, design principle, and evolution of gene regulatory networks involved in the mammalian circadian rhythm.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Tissue distribution of circadian oscillating genes.
(A) Distribution of the number of circadian oscillating genes identified in different numbers of mouse tissues. (B) Distribution of p-values in circular range tests for circadian phases of circadian oscillating genes identified in different numbers of mouse tissues.
Figure 2
Figure 2. Hierarchical clustering of 21 circadian microarray datasets based on global circadian phase dissimilarities.
Datasets are denoted by first author names and tissue types.
Figure 3
Figure 3. Comparison of circadian phases between SCN and liver.
p-values from the circular ANOVA test are indicated in the parenthesis. The solid line represents y = x. The dashed lines represent y = x±6 respectively.
Figure 4
Figure 4. Circadian gene regulatory network in mouse.
(A) Gene regulatory network consisting of the circadian oscillating genes identified in at least 7 mouse tissues. (B) The subset of network highlighting NR3C1 and FKBP/HSP90's role of integrating the regulatory inputs from diverse environmental signals into circadian genes. Blue arrows represent the gene regulatory interactions obtained in this study. Red arrows represent the known gene regulatory or protein interactions extracted from the literature. P stands for phosphorylation. White boxes represent cis-regulatory elements. Colored circles represent the genes with circadian phase information, where circadian phases are represented by the different colors in the color wheel. White circles represent protein complexes or genes without circadian phase information.
See this image and copyright information in PMC

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