Andrew Chuanyin Liu, Ph.D.
PHONE: (352) 392-3791
Liu lab website: www.andrewliulab.org
Google Scholar: https://scholar.google.com/citations?user=EQIuT24AAAAJ&hl=en
PubMed Listing: http://www.ncbi.nlm.nih.gov/sites/myncbi/andrew.liu.2/bibliography/49877736/public/?sort=date&direction=ascending
- Circadian rhythms in mammals
- Biochemistry, genetics, molecular biology, functional genomics
- Behavior, physiology, immunology
In mammals, circadian clocks regulate many aspects of 24-hr rhythms in behavior and physiology, and give organisms an adaptive advantage by preparing for transitions between day and night. In the natural world, the sun’s daily cycle dictates the measure of a day. However, our modern 24/7 life style impose external timing constrains that clash with our internal circadian physiology, often causing health problems (e.g., sleep disorders, accelerated aging, compromised mental performance, metabolic syndrome, cardiovascular diseases, and cancer). The major focus of my lab is to study the molecular, cellular and physiological mechanisms of circadian (~24) clocks in mammals. We ask i) how circadian oscillation is generated in a cell (cell autonomous) and in the central clock in the brain (within a neural network), and ii) how the molecular clock is integrated with cell and organ physiology.
We use cells and animals (mice and rats) as model systems and employ highly integrated approaches to study how the circadian clock keeps time. Circadian oscillation is a single cell phenomenon and the molecular mechanism is encoded in the genome. The clock ticks at multiple levels of circadian organization. Accordingly, we study the clock at the levels of cell, tissue, organ, and the organism. As opposed to traditional methods, we use kinetic (not just steady-state snapshots) and longitudinal methods (multiple days/cycles) to measure the temporal dynamics of molecular, cellular and physiological processes – an important, but largely under-appreciated aspect of biology. For instance, locomotor activity assay is used to study animal behavior and kinetic physiologic monitoring to study physiology. To examine gene expression, we use quantitative PCR, microarray and RNA seq to measure transcript levels. In particular, to study dynamics of gene expression, we engineer luminescent luciferase reporters and introduce them into cells and mice, and bioluminescence rhythms in cells and tissues can be monitored longitudinally through advanced real-time recording.
Leveraging our expertise and a battery of cell and animal clock models, my lab carries out the following main areas of research. i) To probe the biochemical and structural basis of cellular circadian behavior– a complex cellular behavior, and neural network basis of the central SCN clock. ii) To identify novel clock genes and modifiers and characterize how the genes and networks modulate clock function. Our overall strategy for this research is to use cellular clock models for gene discovery and mechanistic studies, and following discovery, gene and protein function will be studied at higher levels of circadian organization including animal behavior. iii) To investigate the extensive, bidirectional integration between the circadian clock and cell physiology, particularly the signaling pathways involved in innate immunity and cancer. While it is well accepted that the clock is anticipatory for time-of-day-dependent physiological needs, this research will uncover how the clock is responsive and adaptive to local physiology – a critically important aspect of proper timekeeping. Recently, we initiated a new line of research to iv) investigate the pathophysiological and neuroendocrine basis of circadian blood pressure regulation and asleep hypertension in the diurnal Nile grass rat model. Knowledge from this model is expected to provide mechanistic insights that would complement understanding from nocturnal animals such as mice.
Scientifically, our goal is to understand the molecular and cellular processes connecting clock genes to circadian physiology and behavior. Ultimately, we hope to gather sufficiently detailed knowledge to be able to effectively modulate our timekeeping system to improve treatments for clock-related disorders and enhance body fitness and health. Finally, I would like point out that physiology and behavior are systems problems, not simple outputs of single genes. In order to obtain integrative understanding, we must study a system using systems approaches: at both single gene/protein and genome-wide levels, and with not only spatial (within and between organs) but also temporal (day vs. night) resolution. As an advisor and mentor, I am acutely aware of the need for future biologists to obtain balanced training and to conduct independent research. I believe our research setup provides such an opportunity for training future generation scientists.
- Welsh DK, Yoo SH, Liu AC, Takahashi JS, Kay SA (2004) Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Current Biology 14: 2289-95 (PMID: 15620658; PMCID: PMC3777438)
- Zhou J*, Liu CY* (co-first author), Back SH, Clark RL, Peisach D, Xu Z#, Kaufman RJ# (#co-senior author) (2006) The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response. Natl. Acad. Sci. USA. 103: 14343-8 (PMID: 16973740; PMCID: PMC1566190)
- Liu AC*, Welsh DK* (co-first author), Ko CH, Tran HG, Zhang EE, Priest AA, Buhr ED, Singer O, Meeker K, Verma IM, Doyle FJ, Takahashi JS, Kay SA (2007) Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell 129: 605-616 (PMID: 17482552; PMCID: PMC3749832)
- Liu AC, Lewis WG, Kay SA (2007) Mammalian circadian signaling networks and therapeutic targets. Nature Chemical Biology 3 (10): 631-640 (PMID: 17876320)
- Liu AC, Tran HG, Zhang EE, Priest AA, Welsh DK, Kay SA (2008) Redundant function of REV-ERB alpha and beta and non-essential role for BMAL1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genetics 4(2): e1000023 (PMID: 18454201; PMCID: PMC2265523)
- Hirota T, Lewis WG, Liu AC, Lee JW, Schultz PG, Kay SA. (2008) A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3 beta. Proc Natl Acad Sci USA 105 (52): 20746–20751 (PMID: 19104043; PMCID: PMC2606900)
- Mirsky HP,Liu AC, Welsh DK, Kay SA, and Doyle FJ. (2009) A model of the cell-autonomous mammalian circadian clock. Proc Natl Acad Sci USA 106: 11107-12 (PMID: 19549830; PMCID: PMC2699375)
- Zhang EE*, Liu AC* (co-first author), Hirota T*, Miraglia LJ,Welch G, Pongsawakul PY, Liu X, Atwood A, Huss JW, Janes J, Su AI, Hogenesch JB# and Kay SA# (#co-senior author) (2009) A Genome-wide siRNA screen for modifiers of the circadian clock in human cells. Cell 139: 199-210 (PMCID: PMC2777987; PMID: 19765810)
- Ko CH, Yamada YR, Welsh DK, Buhr ED, Liu AC, Zhang EE, Ralph MR, Kay SA, Forger D, Takahashi JS (2010) Emergence of noise-induced oscillations in the central circadian pacemaker. PLoS Biology 8(10): e1000513 (PMID: 20967239; PMCID: PMC2953532)
- Zhang EE*, Liu Y* (co-first author), Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy MR# and Kay SA# (#co-senior author) (2010) CRY mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nature Medicine 16, 1152-1156 (PMID: 20852621; PMCID: PMC2952072)
- Ukai-Tadenuma M, Yamada R, Xu H, Ripperger JA, Liu AC and Ueda HR (2011) Delay in feedback repression by Cry1 is required for circadian clock function. Cell144: 268-281 (PMID: 21236481)
- Marpegan L, Swanstrom AE, Chung K, Simon T, Haydon PG, Khan SK, Liu AC, Herzog ED and Beaulé C (2011) Circadian regulation of ATP release in astrocytes. Journal of Neuroscience 31:8342-8350 (PMID: 21653839; PMCID: PMC3135876)
- Ramanathan C, Khan SK, Kathale ND, Xu H, Liu AC (2012) Monitoring cell-autonomous circadian clock rhythms of gene expression using luciferase bioluminescence reporters. Journal of Visualized Experiments (67), e4234 3791/4234 (PMID: 23052244; PMCID: PMC3490247)
- Khan SK, Xu H, Ukai-Tadenuma M, Burton B, Wang Y, Ueda HR and Liu AC (2012) Identification of cryptochrome differentiating domain required for feedback repression in circadian clock function. Journal of Biological Chemistry 287 (31): 25917-26 (PMID: 22692217; PMCID: PMC3406676)
- Evans JA, Pan H, Liu AC, Welsh DK (2012) Cry1-/- circadian rhythmicity depends on SCN intercellular coupling. Journal of Biological Rhythms 27 (6): 443-452 (PMID: 23223370; PMCID: PMC3578226)
- Cao R, Robinson B, Xu H, Gkogkas C, Khoutorsky A, Alain T, Yanagiya A, Nevarko T, Liu AC, Amir S, and Sonenberg N (2013)Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling. Neuron 79(4):712-24 (PMID: 23972597; PMCID: PMC3856944)
- Anafi RC, Lee Y, Sato TK, Venkataraman A, Ramanathan C, Kavakli IH, Hughes ME, Baggs JE, Growe JP, Liu AC, Kim J and Hogenesch JB (2014) Machine learning helps identify CHRONO as a circadian clock component. PLoS Biology 12(4): e1001840 (PMID: 24737000; PMCID: PMC3988006)
- Ramanathan C, Xu H, Khan SK, Shen Y, Gitis PJ, Welsh DK, Hogenesch JB, and Liu AC (2014) Cell type-specific functions of Period genes revealed by novel adipocyte and hepatocyte circadian clock models. PLoS Genetics 10(4): e1004244 (PMID: 24699442; PMCID: PMC3974647)
- Kathale ND and Liu AC (2014) Prevalence of cycling genes and drug targets calls for prospective chronotherapeutics (commentary). Proc Natl Acad Sci USA111: 15869-70 (PMID: 25368193; PMCID: PMC4234540)
- Cao R, Gkogkas CG, Zavalia ND, Blum ID, Yanagiya A, Tsukumo Y, Xu H, Lee C, Storch KF, Liu AC, Amir S# and Sonenberg N# (#co-senior author) (2015). Light-regulated translational control of circadian behavior by eIF4E phosphorylation. Nature Neuroscience 18(6):855-62 (PMID: 25915475; PMCID: PMC4446158)
- Xu H*, Gustafson CL* (co-first author), Sammons PJ, Khan SK, Parsley NC, Ramanathan C, Lee HW, Liu AC# and Partch CL# (#co-senior author) (2015) Cryptochrome 1 regulates the circadian clock through dynamic interactions with the BMAL1 C-terminus, Nature Structure Molecular Biology 22(6):476-84 (PMID: 25961797; PMCID: PMC4456216)
- Xu L, Ruan G, Dai H, Liu AC, Penn J, McMahon DG (2016) Mammalian retinal Müller cells have circadian clock function, Molecular Vision 22:275-283 (PMID: 27081298; PMCID: PMC4812508)
- Zheng Z, Kim H, Qiu, Y, Chen X, Mendez R, Dandekar A, Zhang X, Zhang C, Liu, AC, Yin L, Lin, J, Walker P, Kapatos G, Zhang K (2016) CREBH Couples Circadian Clock with Hepatic Lipid Metabolism, Diabetes 65(11): 3369-3383 (PMID: 27507854; PMCID: PMC5079639)
- Gustafson CL, Parsley NC, Asimgil H, Lee H, Ahlbach C, Michael AK, Xu H, Williams OL, Davis TL, Liu AC, Partch CL (2017) A slow conformational switch in the BMAL1 transactivation domain modulates circadian rhythms, Molecular Cell 66: 447–457 (PMID: 28506462)