Dr. Guoping Fan's research studies the molecular mechanism underlying brain development and function.
Fan's current research focuses on understanding epigenetic mechanisms that regulate neural cell differentiation and adult brain function. He and his colleagues utilize molecular and genetic approaches to investigating how DNA cytosine methylation and its associated components, which include methyl-CpG binding proteins and histone modification enzymes, regulate neural gene expression, cell-lineage differentiation and neural plasticity in development and aging.
Abnormal DNA methylation has been associated with human diseases including cancer and mental retardation disorders. To study the methylation function in the brain, Fan and his associates have used the Cre/loxP conditional gene knockout method to produce transgenic mice that are deficient of the DNA methyltransferase I (Dnmt1) exclusively in the central nervous system (CNS). Dnmt1 deficiency results in DNA hypomethylation in CNS precursor cells and their progeny neuronal and glial cells. The researchers found that DNA hypomethylation induces precocious astroglial cell differentiation in the CNS, suggesting that DNA methylation is a critical determinant in controlling the timing and magnitude of neural cell differentiation. Using DNA microarray technology, the researchers found that a number of neural genes are deregulated in the hypomethylated CNS. Fan and his colleagues are currently defining the molecular mechanism by which DNA hypomethylation alters neuronal gene expression, cell survival and lineage-differentiation in the CNS. Understanding the role of DNA methylation in gene regulation in neural cells will also shed light on the consequence of abnormal DNA methylation on cancer cells.
Selected Cancer-Related Publications:
Liao JL, Yu J, Huang K, Hu J, Diemer T, Ma Z, Dvash T, Yang XJ, Travis GH, Williams DS, Bok D, Fan G. Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells. Hum Mol Genet. 2010 Nov 1;19(21):4229-38. Epub 2010 Aug 13.
Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G. Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci. 2010 Apr;13(4):423-30. Epub 2010 Mar 14.
Hutnick LK, Golshani P, Namihira M, Xue Z, Matynia A, Yang XW, Silva AJ, Schweizer FE, Fan G. DNA hypomethylation restricted to the murine forebrain induces cortical degeneration and impairs postnatal neuronal maturation. Hum Mol Genet. 2009 Aug 1;18(15):2875-88. Epub 2009 May 10.
Fouse SD, Shen Y, Pellegrini M, Cole S, Meissner A, Van Neste L, Jaenisch R, Fan G. Promoter CpG methylation contributes to ES cell gene regulation in parallel with Oct4/Nanog, PcG complex, and histone H3 K4/K27 trimethylation. Cell Stem Cell. 2008 Feb 7;2(2):160-9.
Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun YE. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science. 2003; 302(5646): 890-3.