Abstract
Polymorphisms in the human circadian clock gene PERIOD3 (PER3) are associated with a wide variety of phenotypes such as diurnal preference, delayed sleep phase disorder, sleep homeostasis, cognitive performance, bipolar disorder, type 2 diabetes, cardiac regulation, cancer, light sensitivity, hormone and cytokine secretion, and addiction. However, the molecular mechanisms underlying these phenotypic associations remain unknown. Per3 knockout mice (Per3–/–) have phenotypes related to activity, sleep homeostasis, anhedonia, metabolism, and behavioral responses to light. Using a protocol that induces behavioral differences in response to light in wild type and Per3–/– mice, we compared genome-wide expression in the eye and hypothalamus in the two genotypes. Differentially expressed transcripts were related to inflammation, taste, olfactory and melatonin receptors, lipid metabolism, cell cycle, ubiquitination, and hormones, as well as receptors and channels related to sleep regulation. Differentially expressed transcripts in both tissues co-localized with Per3 on an ∼8Mbp region of distal chromosome 4. The most down-regulated transcript is Prdm16, which is involved in adipocyte differentiation and may mediate altered body mass accumulation in Per3–/– mice. eQTL analysis with BXD mouse strains showed that the expression of some of these transcripts and also others co-localized at distal chromosome 4, is correlated with brain tissue expression levels of Per3 with a highly significant linkage to genetic variation in that region. These data identify a cluster of transcripts on mouse distal chromosome 4 that are co-regulated with Per3 and whose expression levels correlate with those of Per3. This locus lies within a topologically associating domain island that contains many genes with functional links to several of the diverse non-circadian phenotypes associated with polymorphisms in human PER3.
Highlights
The circadian timing system defines biological timing and its synchronization to the environmental 24-h light/dark cycle
We have shown that a primate-specific, variable number, tandem repeat (VNTR), coding region polymorphism in human PER3 is associated with diurnal preference, delayed sleep phase disorder, sleep homeostasis, increased body mass index (BMI) in people who sleep late during work days, cognitive performance, fMRI-assessed brain activity, lower intelligence in people with long sleep duration during work days, and cardiac regulation (Archer et al, 2003; Viola et al, 2007, 2012; Groeger et al, 2008; Vandewalle et al, 2009, 2011; Lazar et al, 2012; Lo et al, 2012)
When mice are exposed to light during their active dark period, they reduce locomotor activity and we have previously shown reduced negative masking in Per3−/− mice compared to WT when exposed to an ultradian light/dark protocol (3.5 h light/3.5 h dark)
Summary
The circadian timing system defines biological timing and its synchronization to the environmental 24-h light/dark cycle. The central pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus entrains to environmental cues and synchronizes peripheral clocks in tissues and organs to regulate 24-h rhythms in physiology and behavior. Its presence is not required for central circadian clock function, absence of PER3 in mice has subtle effects on the circadian period of locomotor activity, and larger effects on the period of circadian gene expression in ex vivo dissociated SCN cells and peripheral organ cell cultures (Shearman et al, 2000; Bae et al, 2001; Pendergast et al, 2012; Ramanathan et al, 2014). Absence of functional PER3 protein in Per knock out mice (Per3−/−) has been associated with reduced inhibition by light of locomotor activity (negative masking), and changes in the overall amount of locomotor activity and sleep homeostasis (van der Veen and Archer, 2010; Hasan et al, 2011)
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