Genetics and Molecular Mechanism of Circadian Rhythm in Mammals

Circadian rhythm is found in phylogenetically distant species from cyanobacteria to human. Circadian rhythm is the organismal adaptation to the daily light-dark cycle as the earth spin around the sun. In human, the most obvious feature of circadian rhythm control is our sleep-wake cycle. At the physiological and biochemical level, the circadian clock controls many of the diurnal cellular and molecular processes including hormonal cycles, cell proliferation and apoptosis in vivo. Pathological effects associated with our circadian clock such as the frequency of asthma attack, heart attack, and strokes are heavily biased towards the early morning.

My laboratory contributed the landmark discoveries by identifying the mammalian Period 1 (mPer1) and Period 2 (mPer2) genes (Sun et al., 1977 and Albretch et al., 1977). Our genetic studies demonstrated that both mPer1 and mPer2 are key circadian regulators (Zheng et al., 1999). Mice genetically engineered to have no mPER1 and mPER2 function have no circadian rhythm and they are completely responsive to external signals such as very short light-dark cycles (see figure below) (Zheng et al., 2001).  One of the research goals in the laboratory is to understand the mechanistic role played by mPER1 and mPER2 in the mammalian circadian clock.

Our studies also demonstrated that mice without circadian clock function are very sensitive to genotoxic stress and are cancer prone. Key cell cycle genes such as c-Myc, Cyclin D1, Cyclin A, Cyclin B, Cdc2, Wee1 are deregulated in temporal expression in circadian mutant mice (Fu et al., 2002).  One of the research interest in the laboratory is the further investigation of circadian rhythm is cell cycle regulation.

Recent studies have implicated that the mechanism of mammalian circadian rhythm is tie to the cellular redox regulation. Our studies demonstrated that aminolevulinate synthase 1 (Alas1) the rate-limiting enzyme for heme biosynthesis is under circadian regulation (Zheng et al., 2001). Our most recent work demonstrated that the prosthetic molecule heme is an important regulator of the circadian clock mechanism in mammals illustrating the reciprocal control between heme biosynthesis and the circadian rhythm mechanism in vivo (Kaasik and Lee 2004). The identification of heme and similar analogs such as cobalamin as clock regulators raises the possibility of porphyrin molecules for therapeutic roles. One of the research interests in the laboratory is the investigation of porphyrin molecules in circadian function.