Distinguished Adjunct Professor
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University
Laboratory: Lab of Stem Cells and Epigenetics
1. Epigenetics in Development and Disease
DNA methylation and histone modifications are key epigenetic factors involved in gene regulation and cell physiology. Dysregulation of DNA methylation and histone modifications has been associated with several human diseases, including Fragile-X, ICF (immunodeficiency, centromere instability, and facial anomaly), Overgrowth, Dwarfism, and Rett Syndromes. To study the function of DNA methylation in development, we have previously used the Cre/loxP system to knockout DNA methyltransferases (Dnmts) tissue-specifically. More recently, we applied the CRISPR-cas9 tool to mutate Dnmts at a single nucleotide resolution to model human genetic mutations in transgenic mice. We are currently defining the molecular mechanism by which DNA methylation alters neuronal gene expression, cell survival, and neuronal function.
2. Stem cells and Translational Medicine
The recent breakthrough of stem cell differentiation and reprogramming provides us with a unique opportunity to model human genetic disorders in stem cells. One of the focuses in our lab is to establish human iPSCs carrying genetic mutations leading to human diseases such as Overgrowth, Dwarfism, and ICF Syndromes that are caused by DNMT3A and DNMT3B point mutations. These human disease-specific iPSCs will be powerful model systems to dissect molecular and epigenetic mechanisms underlying these human diseases.
We also study stem cell differentiation towards specific cell lineages including retinal pigment epithelial cells, corneal endothelial cells, retinal ganglion cells via directed differentiations in 3D-retinoids. By cell transplantation in animal models of retina degeneration, we will test the efficacy of transplanted retinal and corneal cells in the rescue of visual acuity of animal models. Our ultimate goal is to translate our cell transplantation method to treat human patients with blinding diseases such as age-related macular degeneration and retinitis pigmentosa.
Fan G, Egles C, Sun Y, Minichiello L, Renger JJ, Klein R, Liu G, Jaenisch R. Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities. Nat Neurosci. 2000, 3(4):350-7.
Martinowich, K., Hatorri, D., Wu, H., Fouse, S., He, F., Hu, Y., Fan, G.*, Sun, Y.* DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation; Science; 2003 302(5646): 890-3
Feng, J., Zhou, Y., Campbell, S.L., Le, T., Li, E., Sweatt, J.D., Silva, A.J., and Fan, G.* Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons; Nat Neurosci; 2010 13(4): 423-30;
Xue Z#*, Huang K#, Cai C, Cai L, Jiang CY, Feng Y, Liu Z, Zeng Q, Cheng L, Sun YE, Liu JY*, Horvath S, Fan G*. Genetic programs in human and mouse early embryos revealed by single-cell RNA sequencing. Nature. 2013, 500(7464):593-7.
Hu Y#, Huang K#, An Q, Du G, Hu G, Xue J, Zhu X, Wang CY, Xue Z*, Fan G*. Simultaneous profiling of transcriptome and DNA methylome from a single cell. Genome Biol. 2016, 17(1): 88.