Research Interest
Molecular Control of Experience-dependent Gene Expression in Brain Development and Disease
Key Words: Epigenetics, Neurodevelopment, MeCP2, Rett Syndrome, Autism
Description of Research
The developing brain requires a genetic blueprint but also is acutely sensitive to the environment. A fundamental question in Genetics and Neuroscience is how the brain executes genetic programs while maintaining the ability to adapt to environmental stimuli. The underlying molecular mechanisms are not well understood, but epigenetic regulation, mediated by DNA methylation and chromatin organization, may provide an intricate platform to bridge genetics and environment. Impaired epigenetic regulation has been implicated in many brain disorders, including epilepsy, bipolar disorder, schizophrenia, and autism.
Dr. Zhou's research program aims to identify and understand the molecular mechanisms by which environment in the form of experience regulates gene expression and ultimately neurodevelopment in the brain, and how defects in this process may lead to cognitive dysfunction. He recently discovered that MeCP2, a methyl-DNA binding protein mutated in the autism spectrum disorder Rett Syndrome, is dynamically and specifically phosphorylated in the nervous system in response to environmental stimuli. He provided evidence suggesting that experience-dependent phosphorylation of MeCP2 underlies its ability to modulate gene expression and synaptic connectivity. This work has raised the possibility that the epigenetic modifications of the genome may be more dynamic than previously thought and has provided a new paradigm to address the roles of epigenetic components in experience-dependent gene expression and synaptic development. He uses a combination of genomic and proteomic approaches, together with cellular and behavioral assays in transgenic mouse models, to investigate the molecular control of experience-dependent gene expression, as well as to understand the molecular and cellular basis of autism spectrum disorders.
Prior to joining the Department of Genetics, Dr. Zhou was a postdoctoral fellow in the laboratory of Dr. Michael Greenberg at Harvard Medical School and Children’s Hospital Boston. His undergraduate training at Nankai University was in Bioengineering. In 2001 he received his Ph.D. in Molecular and Cellular Biology from Harvard University, where he studied the molecular mechanisms of pre-mRNA splicing and nuclear mRNA export under the joint mentorship of Dr. Robin Reed and Dr. Tom Maniatis. He is a recipient of the 2002 Harold M. Weintraub Graduate Student Award, the Helen Hay Whitney Postdoctoral Fellowship, and the NIH Pathway to Independence Award (K99/R00).
Lab Personnel
Maria Amorim, Research Specialist
Megan Allen, Research Specialist
Darren Goffin, Postdoctoral Fellow
Brian Johnson, Rotation Graduate Student
Aleksandra Nall, Rotation Graduate Student
Arith Reyes, Undergraduate Student
For research opportunities, please email Dr. Zhou.
Selected Publications
Cohen, S., Zhou, Z., and Greenberg, M.E.: Activating a repressor. Science 320: 1172-1173, 2008.
Cukier, H. N., Perez, A. M., Collins, A. L., Zhou, Z., Zoghbi, H. Y., Botas, J.: Genetic modifiers of MeCP2 function in Drosophila. PLoS Genet 4(9): e1000179, 2008.
Zhou, Z., Hong, E. J., Cohen, S., Zhao, W. N., Ho, H. Y., Schmidt, L., Chen, W. G., Lin, Y., Savner, E., Griffith, E. C., Hu, L., Steen, J. A., Weitz, C. J., Greenberg, M. E.: Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52(2): 255-69, 2006.
Zhou, Z., Licklider, L. J., Gygi, S. P., Reed, R.: Comprehensive proteomic analysis of the human spliceosome. Nature 419(6903): 182-5, 2002.
Zhou, Z., Sim, J., Griffith, J., Reed, R.: Purification and electron microscopic visualization of functional human spliceosomes. Proc Natl Acad Sci U S A 99(19): 12203-7, 2002.
Clouse, K. N., Luo, M. J., Zhou, Z., Reed, R.: A Ran-independent pathway for export of spliced mRNA. Nat Cell Biol 3(1): 97-9, 2001.
Luo, M. L., Zhou, Z., Magni, K., Christoforides, C., Rappsilber, J., Mann, M., Reed, R.: Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413(6856): 644-7, 2001.
Das, R., Zhou, Z., Reed, R.: Functional association of U2 snRNP with the ATP-independent spliceosomal complex E. Mol Cell 5(5): 779-87, 2000.
Zhou, Z., Luo, M. J., Straesser, K., Katahira, J., Hurt, E., Reed, R.: The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407(6802): 401-5, 2000.
Zhou, Z., Reed, R.: Human homologs of yeast prp16 and prp17 reveal conservation of the mechanism for catalytic step II of pre-mRNA splicing. Embo J 17(7): 2095-106, 1998.
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Last updated: 10/06/2009
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