Circadian gene expression patterns on the periphery depend on the genotype

author: Rok Košir, Centre for Functional Genomics and Bio-Chips (CFGBC), Institute of Biochemistry, Faculty of Medicine, University of Ljubljana
published: July 21, 2014,   recorded: May 2014,   views: 1518


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Biological clock is an important component in body homeostasis. However, it is not clear how the genetic background of each individual influences circadian expression and regulation. We addressed this question by investigating gene expression in liver and adrenal glands of inbreed mouse strains 129/SvPas plus C57BL/6J and pure C57BL/6J, in dark-dark (DD) or light-dark (LD) conditions.

Mice were sampled in 2-4h intervals over 24h with at least 5 mice per time point. The 24 h gene expression profiles were fitted using various trigonometric functions to obtain the circadian amplitudes and phases. Genome variation data files were downloaded from dbSNP database for the three 129 mouse strains and compared to the reference strain C57BL/6J.

Robustness of the circadian expression depends on the genotype and tissue. In adrenal glands under LD many genes differ in circadian profiles between mouse strains. Steroidogenic genes (Cyp11a1, Cyp17a1, Cyp21a1, Cyp51) are phase-shifted between strains at least in one of the lightening conditions. The majority of steroidogenic and core clock genes are expressed at higher levels with higher amplitudes in 129/SvPas mixed strain, exceptions are Arntl and Cry1. Liver seems to maintain a more robust circadian regulation compared to adrenal glands with fewer differences observed. Since the genomes of 129 and C57BL/6J mice are already sequenced we questioned whether the modified circadian expression derives from mutations in these genes or their regulatory regions. We identified 16.900 sequence variations in 193 selected genes. The majority of variations (> 97%) were discovered in intron and promoter regions. The three 129 strains had the same variations in coding regions of Per3, Vipr2, Opnn4 and Dusp4. Nucleotide variations in were observed also in intron and promoter regions of Per2, RevERBa, Dec2 and Bmal1 that showed differences in phase or amplitudes.

Light has greater impact on circadian expression of core clock and metabolic genes in the 129/SvPas background. Together with the genotype, the light influences primarily the amplitudes of core clock genes while the amplitudes and phases are affected in metabolic genes. 86% of analyzed genes in three different 129 strains harbor genetic variations compared to the reference strain C57BL/6J. The majority of these are in intron and promoter regions that could affect gene expression and thus also the circadian changes observed in our experiment. These findings might have important implications for understanding the genetic bases of the circadian rhythm differences in human individuals and their susceptibility to develop the clock-based diseases.

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