MOLECULAR MECHANISM OF CIRCADIAN RHYTHM & HYPOMETABOLIC BEHAVIORS IN MAMMALS
Circadian rhythm behavior is observed in most living organisms, from microbes to humans. In humans, disruption of circadian function has been associated with disorders of sleep, mood, behavior, metabolic diseases and cancer. Therefore, deciphering the mammalian clock mechanism will provide insight into many fundamental biological processes, as well as various pathological conditions. My laboratory contributed to the landmark discoveries of identifying the mammalian Period 1 (mPer1) and Period 2 (mPer2) genes (Sun et al., 1997 and Albretch et al., 1997). Our genetic studies demonstrated that both mPer1 and mPer2 are key circadian regulators (Zheng et al., 1999). Mice deficient in mPER1 and mPER2 function have no intrinsic circadian rhythm and they are completely entrained to external signals such as very short light-dark cycles (see figure below) (Zheng et al., 2001).
Currently, our investigations are focused in two research areas:
1. Molecular connectivity of the circadian clock mechanism and other cellular pathways
My laboratory is among the first groups to investigate the mechanistic links between clock mechanism, tumor suppression and stress regulatory pathways. Our studies established a role for PER2 in the DNA damage response and tumor suppression (Fu et al., 2002). Recently, we characterized the role of promyelocytic leukemia protein (PML) as a core circadian clock regulator (Miki et al., 2012). In addition, we further revealed that tumor suppressor p53, a major regulator of DNA damage stress response directly regulates the circadian clock via Per2 (Miki et al., 2013). One of the research objectives in the laboratory is to understand the functional implications of these inter-pathway connections.
2. Energy metabolism regulation
The mammalian circadian mechanism has been linked to the cellular redox regulation. Our investigations 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). Knowing redox and heme functions are largely related to metabolic processes, we are interested in the role of circadian clock in hypometabolic behaviors such as hibernations and torpor. Our studies identified genes in peripheral tissues that were activated by constant darkness, an environment encountered by mammals during hibernation. Our studies revealed that such gene activation was associated with the elevation of circulating 5’-adenosine monophosphate (5’-AMP). Mammals given 5’-AMP can enter a deep hypometabolic state that mimics behaviors observed in hibernation and torpor (Zhang et al, 2006). Our studies implicate the erythrocytes to play an important role in AMP induced hypometabolism (Daniels et al., 2010, Daniels et al., 2013). One of the research goals in my laboratory is to further understand the mechanism underlying the 5’-AMP mediated hypometabolic state in mammals.
Albrecht, U., Sun., ZS., J., Eichele, G., and Lee, C.C. A differential response of two putative mammalian circadian regulators mPer1 and mPer2, to light. Cell. 91, 1055-1064 (1997).
Daniels IS, O′Brien WG III, Nath V, Zhao Z, Lee CC. AMP Deaminase 3 Deficiency Enhanced 5′-AMP Induction of Hypometabolism. PLoS ONE. 8(9): e75418. doi:10.1371/journal.pone.0075418 (2013).
Daniels IS, Zhang J, O’Brien WG 3rd, Tao Z, Miki T, Zhao Z, Blackburn MR, and Lee CC. A role of erythrocytes in adenosine monophosphate initiation of hypometabolism in mammals. J. Biol Chem. 285(27):20716-23. (2010)
Fu, L., Pelicano, H., Liu,J., Huang,P., and Lee, C.C. The Circadian Gene Period2 Plays an Important Role in Tumor Suppression and DNA-Damage Response In Vivo. Cell. 111, 41-50 (2002).
Kaasik, K., and Lee, C.C. A Reciprocal Regulation of Heme Biosynthesis and Circadian Clock in Mammals. Nature. 430, 467-471 (2004).
Miki,T., Matsumoto,T., Zhao,Z. and Lee, C.C. p53 Regulates Period2 Expression and the Circadian Clock. Nat. Comm. 4:2444. (2013).
Miki,T., Xu, Z., Chen-Goodspeed, M., Liu, M., Van Oort-Jansen, A., Rea, M.A., Zhao, Z., Lee, C.C.* and Chang, K.S. PML regulates PER2 nuclear localization and circadian function. EMBO J. 2012 Jan 24;31(6):1427-39. (2012) *Corresponding author.
Sun., ZS., Albrecht, U., Zhuchenko, O., Bailey, J., Eichele, G., and Lee, C.C. RIGUI, a putative mammalian ortholog of the Drosophila period gene. Cell. 90, 1003-1011 (1997).
Zhang, J., Kaasik, K., Blackburn, M.R., and Lee, C.C. Constant darkness is a circadian metabolic signal in mammals. Nature. 439, 340-343 (2006).
UTHealth Medical School
Department of Biochemistry and Molecular Biology
6431 Fannin Street, MSB 6.126
Houston, Texas 77030
713-500-6832 Direct 713-500-0652 Fax
PhD - University of Otago, Dunedin, New Zealand.
Postdoctoral Fellow - Baylor College of Medicine, Houston, TX.
Circadian mechanism and Hypometabolism in mammals