Yool Lee, PhD
Department of Translational Medicine and Physiology
PhD, Biological Sciences, Seoul National University , South Korea
MS, Biological Sciences, Seoul National University, South Korea
BS, Biological Sciences, Seoul National University, South Korea
2016 – 2020: Research associate, (PI: Amita Sehgal, PhD) in Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania
2011 – 2016: Postdoctoral researcher, (PI: John Hogenesch, PhD) in Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania
2010-2011: Postdoctoral researcher, (PI: Kyungjin Kim, PhD) in School of Biological Sciences, Seoul National University, South Korea
Our research interest is to study the mechanism underlying the role of circadian clock in physiology and disease therapy. Circadian clocks are cellular timing systems that generate 24-hour biological rhythms that are conserved in nearly all life from unicellular organisms to humans. The internal body clock integrates with diverse environmental and metabolic stimuli (e.g., light, foods) to organize daily rhythms of behavior (e.g. sleep/wake and feeding cycles), physiology (e.g. body temperature, hormonal and immune systems), and cellular processes (e.g. the metabolic and cell cycle pathways). In modern society, circadian rhythm misalignments such as sleep deprivation, jet lag and shift work are thought to increase susceptibility to metabolic (e.g. cancer, obesity, and type 2 diabetes) and neurodegenerative (e.g. Alzheimer’s and Parkinson’s diseases) disorders. Conversely, such pathological disorders are increasingly known to disrupt the sleep-wake cycle and circadian physiology. Thus a detailed understanding of the regulatory pathways of the circadian clock and how these interplay with various disease processes is crucial for the prevention and treatment of clock-associated disorders.
In this regard, our current studies include: (1) Understanding the biological mechanisms of circadian physiology and behaviors; (2) Investigating the molecular and cellular impact of circadian disruptions on tumor heterogeneity, tumor microenvironment, and metastatic progression in human osteosarcoma and melanoma. (3) Translational applications of circadian physiology for the treatment of cancer and aging-related pathologies using nutritional, metabolic, and pharmacological interventions. For these research, our lab is applying or developing various experimental models and approaches with the combined use of the following analysis tools.
- Genetic and molecular analysis: CRISPR/Cas9 genome editing and RNAi knock-down technology for genetic perturbation analysis of cellular rhythms. PCR-based molecular DNA cloning for functional analysis of target gene. Quantitative real-time PCR for endogenous gene expression analysis. RNA sequencing analysis of global gene expression profiles in cells or tissues.
- Biochemical analysis: Western blot (WB) for protein expression of the target gene, Immunoprecipitation (IP) for protein-protein interaction analysis, Chromatin immunoprecipitation (ChIP) analysis for protein-DNA binding.
- Real-time 2D/3D cell and tissue culture analysis: 1) Förster Resonance Energy Transfer (FRET)/Biomolecular Fluorescence Complementation (BiFC) assays for real-time live cell imaging of protein-protein interaction. 2) Time-lapse cell cycle analysis using fluorescence ubiquitination cell cycle indicator (FUCCI) system. 2) Real-time fluorescence imaging of cancer cell evolution using fluorescence reporters of cancer stem cell (CSC) and/or epithelial-to-mesenchymal transition (EMT) phenotypes in monolayer or 3D cultured cancer cells. Real-time bioluminescence recording of circadian rhythms in clock gene promoter-driven luciferase reporter cells (e.g. pPer2/pBmal1-dsLuc) or transgenic mouse tissues (e.g. pPer2-Luc knock-in mice). Fluorescence-Activated Cell Sorting (FACS) and immunohistochemistry (IHC) analyses of 3D cultured or mouse xenografted tumors.
- Metabolic analysis: Measurement of cellular energy metabolisms such as glycolysis and mitochondrial respiration, and oxidative stress levels using Metabolic Flux Analyzer or fluorescence-based indicators.
- Pharmacological analysis: High-throughput measurement of dose and time-dependent efficacy of synthetic or natural therapeutic compounds or their treatment effect on circadian rhythms in cells using an automatic muli-mode plate reader.
- In vivo imaging analysis: Live-animal imaging or recording analysis of bioluminescence reporter transgenic mice (e.g. pPer2-Luc knock-in) using IVIS Spectrum In Vivo Imaging System or Lumicycle In vivo.
- Behavioral analysis: Real-time long-term measurement of daily locomotor activity of mice housed in circadian chamber instruments under various settings of circadian environments.
2008 Grant award by National Research Foundation of Korea
Lee Y, Wisor JP. Multi-Modal Regulation of Circadian Physiology by Interactive Features of Biological Clocks. Biology (Basel). 2021 Dec 24;11(1). doi: 10.3390/biology11010021. Review. PubMed PMID: 35053019; PubMed Central PMCID: PMC8772734.
Lee Y. Roles of circadian clocks in cancer pathogenesis and treatment. Exp Mol Med. 2021 Oct;53(10):1529-1538. doi: 10.1038/s12276-021-00681-0. Epub 2021 Oct 7. Review. PubMed PMID: 34615982; PubMed Central PMCID: PMC8568965.
Lee Y, Field JM, Sehgal A. Circadian Rhythms, Disease and Chronotherapy. J Biol Rhythms. 2021 Dec;36(6):503-531. doi: 10.1177/07487304211044301. Epub 2021 Sep 22. Review. PubMed PMID: 34547953; PubMed Central PMCID: PMC9197224.
Lee Y, Fong SY, Shon J, Zhang S, Brooks R, Lahens NF, Chen D, Dang CV, Field JM, Sehgal A. 2021. Time-of-day specificity of anti-cancer drugs may be mediated by circadian regulation of the cell cycle. Science Advances. 7, eabd2645. doi: 10.1126/sciadv.abd2645. PMID: 33579708.
Lee Y, Shen Y, Francey LJ, Ramanathan C, Sehgal A, Liu AC, Hogenesch JB. The NRON complex controls circadian clock function through regulated PER and CRY nuclear translocation. Sci Rep. 2019 Aug 15;9(1):11883. doi: 10.1038/s41598-019-48341-8. PubMed PMID: 31417156; PubMed Central PMCID: PMC6695496.
Lee Y, Lahens NF, Zhang S, Bedont J, Field JM, Sehgal A. G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment. PLoS Biol. 2019 Apr;17(4):e3000228. doi: 10.1371/journal.pbio.3000228. eCollection 2019 Apr. PubMed PMID: 31039152; PubMed Central PMCID: PMC6490878.
Bai L, Lee Y, Hsu CT, Williams JA, Cavanaugh D, Zheng X, Stein C, Haynes P, Wang H, Gutmann DH, Sehgal A. A Conserved Circadian Function for the Neurofibromatosis 1 Gene. Cell Rep. 2018 Mar 27;22(13):3416-3426. doi: 10.1016/j.celrep.2018.03.014. PubMed PMID: 29590612; PubMed Central PMCID: PMC5898822.
Havekes R, Park AJ, Tolentino RE, Bruinenberg VM, Tudor JC, Lee Y, Hansen RT, Guercio LA, Linton E, Neves-Zaph SR, Meerlo P, Baillie GS, Houslay MD, Abel T. Compartmentalized PDE4A5 Signaling Impairs Hippocampal Synaptic Plasticity and Long-Term Memory. J Neurosci. 2016 Aug 24;36(34):8936-46. doi: 10.1523/JNEUROSCI.0248-16.2016. PubMed PMID: 27559174; PubMed Central PMCID: PMC4995304.
Lee Y, Chun SK, Kim K. Sumoylation controls CLOCK-BMAL1-mediated clock resetting via CBP recruitment in nuclear transcriptional foci. Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2697-708. doi: 10.1016/j.bbamcr.2015.07.005. Epub 2015 Jul 9. PubMed PMID: 26164627.
Lee Y, Jang AR, Francey LJ, Sehgal A, Hogenesch JB. KPNB1 mediates PER/CRY nuclear translocation and circadian clock function. Elife. 2015 Aug 29;4. doi: 10.7554/eLife.08647. PubMed PMID: 26319354; PubMed Central PMCID: PMC4597257.
Park I, Lee Y, Kim HD, Kim K. Effect of Resveratrol, a SIRT1 Activator, on the Interactions of the CLOCK/BMAL1 Complex. Endocrinol Metab (Seoul). 2014 Sep;29(3):379-87. doi: 10.3803/EnM.2014.29.3.379. Epub 2014 Sep 25. PubMed PMID: 25309798; PubMed Central PMCID: PMC4192820.
Anafi RC, Lee Y, Sato TK, Venkataraman A, Ramanathan C, Kavakli IH, Hughes ME, Baggs JE, Growe J, Liu AC, Kim J, Hogenesch JB. Machine learning helps identify CHRONO as a circadian clock component. PLoS Biol. 2014 Apr;12(4):e1001840. doi: 10.1371/journal.pbio.1001840. eCollection 2014 Apr. PubMed PMID: 24737000; PubMed Central PMCID: PMC3988006.
Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn JT, Culver JP, Herzog ED, Hogenesch JB, Wozniak DF, Dikranian K, Giasson BI, Weaver DR, Holtzman DM, Fitzgerald GA. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J Clin Invest. 2013 Dec;123(12):5389-400. doi: 10.1172/JCI70317. Epub 2013 Nov 25. PubMed PMID: 24270424; PubMed Central PMCID: PMC3859381.
Lee Y, Kim K. Posttranslational and epigenetic regulation of the CLOCK/BMAL1 complex in the mammalian. Animal cells and systems. 2012; 16(1):1-10. doi: 10.1080/19768354.2011.603749.
Lee Y, Lee J, Kwon I, Nakajima Y, Ohmiya Y, Son GH, Lee KH, Kim K. Coactivation of the CLOCK-BMAL1 complex by CBP mediates resetting of the circadian clock. J Cell Sci. 2010 Oct 15;123(Pt 20):3547-57. doi: 10.1242/jcs.070300. PubMed PMID: 20930143.
Lee J, Lee Y, Lee MJ, Park E, Kang SH, Chung CH, Lee KH, Kim K. Dual modification of BMAL1 by SUMO2/3 and ubiquitin promotes circadian activation of the CLOCK/BMAL1 complex. Mol Cell Biol. 2008 Oct;28(19):6056-65. doi: 10.1128/MCB.00583-08. Epub 2008 Jul 21. PubMed PMID: 18644859; PubMed Central PMCID: PMC2546997.
Eun B, Lee Y, Hong S, Kim J, Lee HW, Kim K, Sun W, Kim H. Hes6 controls cell proliferation via interaction with cAMP-response element-binding protein-binding protein in the promyelocytic leukemia nuclear body. J Biol Chem. 2008 Feb 29;283(9):5939-49. doi: 10.1074/jbc.M707683200. Epub 2007 Dec 26. PubMed PMID: 18160400.
A complete list of published works can be found here.