Dr. Zheng (Jake) Chen, Assistant Professor

Department of Biochemistry and Molecular Biology

University of Texas-Houston Medical School
MSB 6.128 Houston, Texas 77030
(713) 500-6284 - Fax (713) 500-0652
email: zheng.chen.1@uth.tmc.edu

Ph.D. Columbia University, New York
Postdoctoral Fellow, UT Southwestern, Dallas

function and regulation of biological clocks

Biological clocks exert temporal control over essential cellular and physiological processes in diverse organisms. Conversely, dysregulated clocks have been associated with a number of chronic diseases. In our previous studies, we showed that impaired cell cycle gating by the metabolic cycle in yeast has been shown to result in highly elevated mutation rate, and a conserved DNA damage response pathway may serve to couple the cell cycle to the metabolic and circadian cycles (Chen et al., 2007a and 2007b). In mammals, while the general feature of the circadian clock is well-established, much of the detailed mechanism underlying the function and regulation of the clock remains poorly defined.

Our lab employs an integrative approach to address the above problem. In particular, we are interested in developing a research platform combining high-throughput screening (HTS) and chemical genetic tools. Taking advantage of robust assays and small compound libraries encompassing broad chemical space, we expect to identify small molecules that can specifically and potently manipulate the clock. To investigate the modes of action of these compounds, we will perform biochemical purification and genetic screening to identify protein/gene targets.

1. High-throughput chemical screening to identify clock-resetting compounds
Previously, a high-throughput screen was conducted using a canonical luciferase reporter in a cell-based assay, and a group of compounds were found to selectively alter the period, phase and/or amplitude of the circadian cycle (Fig. 1). Importantly, a number of compounds were further validated by their efficacy on ex vivo circadian clocks. We are currently developing second-generation screening assays aiming for compounds that can directionally target specific components or attributes of the clock.

2. Identification of the target and mechanism of hit compounds
It has been a long-standing challenge to identify molecular targets of hit compounds that exhibit activities in cell-based assays. To tackle this problem, we are developing a two-pronged approach. In collaboration with synthetic chemists, we will perform biochemical pull-down using biotinylated derivatives of the above hit compounds. Alternatively, hit compounds will be administered to genetic mutant libraries to identify genes whose alteration rescues or exacerbates the clock effects.

Dose responses of compounds that specifically affect the period, phase and/or amplitude of the mammalian circadian clock. Blue: vehicle control; purple, green and red: compounds at 0.5, 1.5 and 5 uM, respectively. X-axis values represent reporter luciferase reading.

Chen, Z., Yoo, S., Buhr, E., Estill, S.J., Ferster, D., Takahashi, J.S., and McKnight, S.L. Identification of small chemical compounds capable of modulating the mammalian circadian clock. In preparation.
Chen, Z., Tu, B.P., and McKnight, S.L., 2009. Biological and medical relevance of circadian and metabolic cycles. Seasonal Affective Disorder, 2nd ed., Oxford University Press. Eds. T. Partonen and S. R. Pandi-Perumal. Invited book chapter. In press.
Chen, Z., Odstrcil, E.A., Tu, B.P., and McKnight, S.L., 2007a. Restriction of nuclear DNA replication to the reductive phase of the metabolic cycle protects genome integrity. Science 316, 1916-1919.
Chen, Z., McKnight, S.L., 2007b. A conserved DNA damage response pathway responsible for coupling the cell division cycle to the circadian and metabolic cycles. Cell Cycle 6, 2906-2912.
Chen, Z. and Manley, J.L., 2003. Core promoter elements and TAFs contribute to the diversity of transcriptional activation in vertebrates. Mol. Cell Biol. 23, 7350-7362.
Chen, Z. and Manley, J.L., 2003. In vivo analysis of the histone 3-like TAF9 and a TAF9-related factor, TAF9L. J. Biol. Chem. 278, 35172-35183.
Chen, Z. and Manley, J.L., 2000. Robust mRNA transcription in chicken DT40 cells depleted of TAF31 suggests both functional degeneracy and evolutionary divergence. Mol. Cell Biol. 20, 5064-5076.