Our laboratory has been using molecular, cellular biological tools and genetic models to study biological rhythm and energy metabolic regulation. Currently, my laboratory are mainly focused in two research areas:
The daily rhythmic behavioral pattern of many living organisms is ultimately driven by an endogenous molecular clock, the circadian clock. Circadian is a word derived from Latin words circa meaning “about”, and dies meaning “day”. The circadian clock exerts temporal regulation of biological process at the molecular, cellular, and physiological levels. 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, 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 (Zheng et al., 2001). We are continuing our studies to further understand the molecular actions of PER1 and PER2 in the circadian mechanism.
Over the past decade or so, my laboratory was among the first groups to investigate the molecular links between clock mechanism and other cellular pathways. Our studies established a role for PER2 in the DNA damage response and tumor suppression (Fu et al., 2002). Our more recent studies characterizing circadian regulatory roles of two human tumor
suppressors promyelocytic leukemia protein (PML) and p53, as well as metastasis associated 1 (MTA1) provided additional direct links between clock function, tumor suppression and stress regulatory pathways (Miki et al., 2012; Miki et al., 2013, Li et al., 2013). We are continuing our investigation of the interactions among these proteins and core clock proteins (Miki et al., 2016), as well as elucidating the biological implications of these inter-pathway connections.
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). PMID: 9428527
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). PMID: 12372299
Li, D.Q., Pakala, S.B., Reddy, S.D., Peng, S., Balasenthil, S., Deng, C.X., Lee C.C., Rea, M.A., Kumar, R. Metastasis-associated protein 1 is an integral component of the circadian molecular machinery. Nat Commun. 4:2545. doi: 10.1038/ncomms3545. (2013). PMID: 24089055
Miki T, Zhao Z, Lee C.C. Interactive Organization of the Circadian Core Regulators PER2, BMAL1, CLOCK and PML. Sci. Rep. 6:29174; doi: 10.1038/srep29174 (2016). PMID: 27383066
Miki, T., Matsumoto, T., Zhao, Z. and Lee, C.C. p53 Regulates Period2 Expression and the Circadian Clock. Nat. Commun. 4:2444. (2013). PMCID: PMC3798035
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. 31(6):1427-39. (2012) Corresponding author. PMCID: PMC3321181
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). PMID: 9323128
Zheng, B., Larkin, D.W., Albrecht, U., Sun, Z.S., Sage, M., Eichele, G., Lee, C.C*., and Bradley, A. mPer2 encodes a functional component of the mammalian circadian clock. Nature. 400,169-73 (1999). * Corresponding author. PMID: 10408444
Zheng., B., Albrecht, U., Kaasik, K., Sage, M, Weiqin Lu., Vaishnav, Qui, Li., S, Sun, Z.S, Eichele, G., Bradley, A., and Lee, C.C. Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell. 105, 683-694 (2001). PMID: 11389837
The mammalian circadian mechanism has been linked to cellular redox regulation. Our investigations demonstrated that the heme is an important regulator of the circadian clock mechanism in mammals, exhibiting reciprocal control between heme biosynthesis and the circadian rhythm mechanism in vivo (Kaasik and Lee 2004). Since redox and heme functions are largely related to metabolic processes, we are interested in the role of the circadian clock in hypometabolic behaviors such as hibernation 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 a key role for erythrocytes in AMP induced hypometabolism (AIHM) (Daniels et al., 2010, Daniels et al., 2013, O’Brien et al., 2015). Our studies demonstrated that AIHM is a safe and reversible process (Zhao et al., 2011 & 2013). Therefore, we have explored the potential of AIHM in therapeutic applications of hypometabolism (Tao et al., 2011, Zhang et al., 2015). One of the research goals in my laboratory is to further understand the mechanism underlying the 5’-AMP mediated hypometabolic state in mammals.
Daniels IS, O′Brien WG III, Nath V, Zhao Z, Lee C.C. 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)
Kaasik, K., and Lee, C.C. A Reciprocal Regulation of Heme Biosynthesis and Circadian Clock in Mammals. Nature. 430, 467-471 (2004).
O’Brien, W.G. III, Berka, V., Tsai, A.L., Zhao, Z. and Lee, C.C. CD73 and AMPD3 deficiency enhance metabolic performance via erythrocyte ATP that decreases hemoglobin oxygen affinity. Sci. Rep. 5, 13147; doi: 10.1038/srep13147 (2015). PMID: 26249166.
Tao, Z, Zhao, Z and Lee, C.C. 5′- Adenosine Monophosphate Induced Hypothermia Reduces Early stage Myocardial Ischemia/Reperfusion Injury in a Mouse Model. Am J Transl Res. 3(4):351-361. (2011). PMID: 21904655
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).
Zhang, Y., O’Brien, W.G., III, Zhao, Z., Lee, C.C. 5′-Adenosine Monophosphate Mediated Cooling Treatment Enhances ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Stability in vivo. J Biomed Sci. 4;22(1):72. (2015). PMID: 26335336.
Zhao Z, Miki T, Van Oort-Jansen A, Matsumoto T, Loose DS, Lee C.C. Hepatic Gene Expression Profiling of 5′-AMP Induced Hypometabolism in Mice. Physiol Genomics. 43(7):325-45. (2011) PMCID: PMC3092333
Zhao, Z., Van Oort, A., Tao, Z., and Lee C.C. Metabolite Profiling of 5′-AMP-Induced Hypometabolism. Metabolomics. 10(1):63-76 (2014). PMCID: PMC3913270
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
Nat Commun. 2013;4:2444. doi: 10.1038/ncomms3444.
PMCID: PMC3798035read more
Sci Rep. 2015 Aug 7;5:13147. doi: 10.1038/srep13147
PMID: 26249166read more
EMBO J. 2012 Mar 21;31(6):1427-39. doi: 10.1038/emboj.2012.1. Epub 2012 Jan 24.
PMCID: PMC3321181read more