Tissue-Specific Interaction of Per1/2 and Dec2 in the Regulation of Fibroblast Circadian Rhythms

Dec 11, 2012Journal of biological rhythms

How Per1/2 and Dec2 interact differently in tissues to control daily rhythms in fibroblast cells

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Abstract

Fibroblasts from mutant mice reveal tissue-specific interactions between clock genes Per1, Per2, and Dec2.

The interaction between Per genes and Dec2 operates in a synergistic manner at the cellular level.
Deletion of Dec2 in Per2 mutant cells restores rhythmicity, suggesting it destabilizes clock function without Per2.
Rhythm power is significantly reduced in double mutants of Per1/Dec2 and Per2/Dec2, indicating the importance of Dec2 in stabilizing clock period.
Nonsynergistic effects on cellular clock phase regulation from Dec2 and Per1/2 mutations do not align with period effects.
Interactions of Per1/2 and Dec2 vary by cell type, highlighting the complex architecture of the mammalian circadian clock.

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In mammals, the molecular circadian clockwork is comprised of interlocked transcriptional-translational feedback loops (TTLs). Three Period (Per1-3) and 2 Dec (Dec1/2) genes interact in regulating the activity of the transcriptional activators CLOCK/NPAS2 and BMAL1. While deletion of Per1 and Per2 in mice results in behavioral arrhythmicity, Dec deletion has less dramatic effects on activity rhythms, affecting primarily phase of entrainment and free-running period. In intact animals, clock gene mutant phenotypes are often masked due to intercellular coupling mechanisms that stabilize cellular rhythms. Therefore, to study Per/Dec genetic interaction at the cellular level, we isolated fibroblasts from different tissues of Per1, Per2, and Dec2 single and double mutant mice. We show that in the cellular TTL, Pers and Dec2 act in a principally synergistic way, but tissue-specific differences in this interaction are seen. A rescue of rhythmicity in Per2 mutant cells after additional deletion of Dec2 was observed, indicating that in the absence of Per2, DEC2 destabilizes TTL function. Rhythm power in Per1/Dec2 and Per2/Dec2 double mutants was strongly reduced, suggesting that interaction of Dec2 with both Per genes is important for stabilizing clock period. Contrary to what was observed for behavior, nonsynergistic effects of Dec2 and Per1/2 mutations were observed on cellular clock phase regulation that do not correlate with period effects. Our data reveal cell type-specific interactions of Per1/2 and Dec2 in the regulation of period, phase, and rhythm sustainment, emphasizing the differential organization of the mammalian clock machinery in different tissues.

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Tissue-Specific Interaction of Per1/2 and Dec2 in the Regulation of Fibroblast Circadian Rhythms

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