Explore Genetic Determinants For Clock Amplitude And Entrainment

As light cycle changes on earth,a diverse range of species,from cyanobacteria to humans,have evolved endogenous circadian systems to anticipate environment variations.Circadian clock allows organisms to better capitalize on environmental resources suchas food,and escape from their predators,as opposedto those arrhythmic ones.Thus,our internal physiology and biological function are highly associated with the circadian clock.The mammalian circadian clock is composed of a transcriptional-translational feedback loop.In the core mammalian circadian negative feedback loop,the activator BMAL1 and CLOCK can activate the transcription of Period(Per),Cryptochrome(Cry),and clock-controlled genes by binding to E-boxes in their promoters.In contrast,to close the negative feedback loop,PER and CRY can bind with BMAL1-CLOCK and inhibit their transcriptions.Moreover,a secondary feedback loop consists of the orphan nuclear receptors REVERBa/b and retinoid-related orphan receptor(RORs),which act on the Rev-Erb/ROR-binding element(RREs)to regulate Bmall and Cry1 expression.In section one,we used liver-specific knockout HDAC3 mouse model and found histone deacetylase 3(HDAC3)is a critical component of the circadian negative feedback loop that is regulating both the activation and repression processes in a deacetylase activity-independent manner.Genetic depletion of Hdac3 in mouse liver results in low-amplitude circadian rhythms and dampens E-box-driven transcription.In subjective morning,HDAC3 is required for the efficient transcriptional activation process by regulating BMAL1 stability through promoting BMAL1 ubiquitination.In subjective night,however,HDAC3 blocks FBXL3-mediated CRYI degradation and promotes BMAL1 and CRY1 association.Therefore,these two opposing but temporally separated roles of HDAC3 in the negative feedback loop provide a mechanism for robust circadian gene expression.In section two,we used International Mouse Phenotyping Consortium(IMPC)metabolic chamber data resources.We determined the onset time and peak phase of activity/food intake rhythms as the reliable and quantifiable biomarkers for an improper circadian entrainment based on the analysis of parameters of indirect calorimetry from more than 1200 C57BL/6N mice.Then,we developed algorithms incorporating previous knowledge to carry out a large-scale screening by taking advantage of international mouse phenotyping consortium(IMPC)resources.We identifiedSlc7A11,Rhbdll,Spop,and Oxtr genes from 515 unselected mutant strains for their change in the onset and phase shifts of activity/food intake by validation.The screening hits involve in distinct pathways either circadian-dependent or independent way but tightly interconnected with circadian systems.These signaling routes provide potential targets for the regulation of circadian entrainment.