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Analysis of gene regulatory networks in the mammalian circadian rhythm.

Yan J, Wang H, Liu Y, Shao C - PLoS Comput. Biol. (2008)

Bottom Line: Here we try to address these questions by integrating all available circadian microarray data in mammals.We observed the significant association of cis-regulatory elements: EBOX, DBOX, RRE, and HSE with the different phases of circadian oscillating genes.Our study improves our understanding of the structure, design principle, and evolution of gene regulatory networks involved in the mammalian circadian rhythm.

View Article: PubMed Central - PubMed

Affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Shanghai, China. junyan@picb.ac.cn

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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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.
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pcbi-1000193-g004: 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.

Mentions: Based on these regulatory interactions, we constructed the gene regulatory network for the circadian oscillating genes in mouse. In Figure 4, we show a network consisting of the circadian oscillating genes identified in at least 7 mouse tissues. Among the 81 circadian oscillating genes identified in at least 7 tissues, 53 of them can be included through 88 regulatory interactions with 9 cis-regulatory elements in our network. Their circadian phases were represented by different colors in the color wheel. We were able to identify almost all known transcription regulatory interactions for common circadian genes in the literature, except EBOX → Per1, EBOX → Nr1d1, EBOX → Ppara, RRE → Nr1d1, and RRE → Cry1. To further complete our network, we supplemented these missing gene regulatory interactions with known protein interaction information (Per/Cry Arntl/Clock and Fkbp:Hsp90 Nr3c1) and protein phosphorylation information (Csnk1d → Per/Cry and Gsk3b → Nr1d1) from the literature. These relationships are shown in red color in Figure 4.


Analysis of gene regulatory networks in the mammalian circadian rhythm.

Yan J, Wang H, Liu Y, Shao C - PLoS Comput. Biol. (2008)

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.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2543109&req=5

pcbi-1000193-g004: 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.
Mentions: Based on these regulatory interactions, we constructed the gene regulatory network for the circadian oscillating genes in mouse. In Figure 4, we show a network consisting of the circadian oscillating genes identified in at least 7 mouse tissues. Among the 81 circadian oscillating genes identified in at least 7 tissues, 53 of them can be included through 88 regulatory interactions with 9 cis-regulatory elements in our network. Their circadian phases were represented by different colors in the color wheel. We were able to identify almost all known transcription regulatory interactions for common circadian genes in the literature, except EBOX → Per1, EBOX → Nr1d1, EBOX → Ppara, RRE → Nr1d1, and RRE → Cry1. To further complete our network, we supplemented these missing gene regulatory interactions with known protein interaction information (Per/Cry Arntl/Clock and Fkbp:Hsp90 Nr3c1) and protein phosphorylation information (Csnk1d → Per/Cry and Gsk3b → Nr1d1) from the literature. These relationships are shown in red color in Figure 4.

Bottom Line: Here we try to address these questions by integrating all available circadian microarray data in mammals.We observed the significant association of cis-regulatory elements: EBOX, DBOX, RRE, and HSE with the different phases of circadian oscillating genes.Our study improves our understanding of the structure, design principle, and evolution of gene regulatory networks involved in the mammalian circadian rhythm.

View Article: PubMed Central - PubMed

Affiliation: CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Shanghai, China. junyan@picb.ac.cn

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.

Show MeSH
Related in: MedlinePlus