Shen, Y., Matsuno, Y., Fouse, S., Rao, N., Root, S., Xu, R.H., Pellegrini, Riggs, A., Fan, G. X-inactivation in female human embryonic stem cells is in a non-random pattern and prone to epigenetic alterations. .
Proc. Natl. Acad. Sci. USA
2008;
105(12):
4709-4714.
Fouse, S., 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;
2(2):
160-169.
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Golshani, P., Hutnick, L., Schweizer, F., Fan, G. Conditional Dnmt1 deletion in dorsal forebrain disrupts development of somatosensory barrel cortex and thalamocortical long-term potentiation.
Thalamus and Related System .
2007;
Published online in March 2007:
.
Feng, J., Fouse, S., Fan, G. Epigenetic regulation of neural gene expression and neuronal function.
Pediatric Research.
2007;
61 (5 Pt 2):
58R-63R.
Shen Y, Chow J, Wang Z, FanG Abnormal CpG island methylation occurs during in vitro differentiation of human embryonic stem cells. .
Human Molecular Genetics.
2006;
15(17):
2623-2635.
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He F, Ge W, Zhu W, Becker-Catania S, Martinowich K, Wu H, Coskun V, Fan G, deVellis J, Sun Y A positive autoregulation loop of JAK-STAT signaling is part of the clock mechanism regulating astrogliogenesis..
Nature Neuroscience
2005;
8:
616-625.
Lyckman AW, Fan G, Rios M, Jaenisch R, Sur M Normal eye-specific patterning of retinal inputs to murine subcortical visual nuclei in the absence of brain-derived neurotrophic factor..
Visual neuroscience. .
2005;
22(1):
27-36.
Fan G, Martinowich K, Chin MH, He F, Fouse SD, Hutnick L, Hattori D, Ge W, Shen Y, Wu H, ten Hoeve J, Shuai K, Sun YE DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling..
Development (Cambridge, England) .
2005;
132(15):
3345-56.
Fan G, Hutnick L Methyl-CpG binding proteins in the nervous system..
Cell research. .
2005;
15(4):
255-61.
Feng J, Chang H, Li E, Fan G Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system.
J Neurosci Res.
2005;
79:
734-746 (Cover art).
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.
Ge W, Martinowich K, Wu X, He F, Miyamoto A, Fan G, Weinmaster G, Sun YE Notch signaling promotes astrogliogenesis via direct CSL-mediated glial gene activation..
Journal of neuroscience research. .
2002;
69(6):
848-60.
Fan G, Beard C, Chen RZ, Csankovszki G, Sun Y, Siniaia M, Biniszkiewicz D, Bates B, Lee PP, Kuhn R, Trumpp A, Poon C, Wilson CB, Jaenisch R DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals..
The Journal of neuroscience : the official journal of the Society for Neuroscience. .
2001;
21(3):
788-97.
Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, Greenberg ME Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms..
Cell. .
2001;
104(3):
365-76.
Fan G, Copray S, Wong E, Yan Q, Jones K, Walro J, Jaenisch R, Kucera J Formation of the cranial proprioceptive system requires multiple neurotrophins..
Developmental Dynamics
2000;
218:
359-370.
Endres M, Fan G (equal contribution), Hirt L, Fujji M, Liu X, Jaenisch R, Moskowitz MA Ischemic brain damage after selectively modifying BDNF or NT-4 expression in vivo..
J. Cereb.Blood Flow. Metab.
2000;
20:
139-144.
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..
Nature neuroscience. .
2000;
3(4):
350-7.
Fan G, Xiao L, Cheng L, Wang X, Sun B, Hu G Targeted disruption of NDST-1 gene leads to pulmonary hypoplasia and neonatal respiratory distress in mice..
FEBS letters. .
2000;
467(1):
7-11.
Bates B, Rios M, Trumpp A, Chen C, Fan G, Bishop JM, Jaenisch R Neurotrophin-3 is required for proper cerebellar development..
Nature neuroscience. .
1999;
2(2):
115-7.
Fan G, Jaenisch R, Kucera J A role for p75 receptor in NT3 functioning during the development of limb proprioception..
Neuroscience
1999;
90:
259-268.
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Our current research focuses on understanding epigenetic mechanisms that regulate neural stem cell differentiation and adult neural function. We 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.
1). DNA methylation in neural development and function:
Abnormal DNA methylation has been associated with several human mental retardation disorders, including fragile-X, ICF, and Rett Syndromes. To study the methylation function in the brain, we 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) (J. Neuroscience 21:788-797). Dnmt1 deficiency results in DNA hypomethylation in CNS precursor cells and their progeny neuronal and glial cells. We 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, we found that a number of neural genes are deregulated in the hypomethylated CNS. We are currently defining the molecular mechanism by which DNA hypomethylation alters neuronal gene expression (Science 302: 890-893), cell survival, and lineage-differentiation in the CNS (Development 132:3345-3356).
2). Epigenetic mechanisms control in vitro differentiatoin of embryonic stem (ES) cells:
ES cells are pluripotent and can be induced to differentiate into multiple somatic cell lineages in vitro. However, mechanisms underlying directed differentiation of ES cells are poorly understood. To examine whether cell lineage-specific differentiation of ES cells is regulated by epigenetic factors such as DNA methylation, we have established a culture system to induce sequential neuronal and glial differentiation with mouse and human ES cells. Because ES cell lines are particularly amenable to genetic manipulation, we can generate and utilize mutant ES cell lines to analyze the involvement of epigenetic factors in neural cell differentiation in vitro. We have found that mouse de novo DNA methyltransferases Dnmt3a and Dnmt3b are required for suppressing astroglial differentiation and silencing glial cell lineage genes during the early neurogenic phase of ES cell differentiation. Our short-term goal is to define the changes in DNA methylation and histone modifications during neural differentiation of ES cells. We also devise methods to achieve high efficiency neuronal differentiation with mouse and human ES cells through genetic and/or pharmacological interventions of DNA methylation and chromatin modifications.
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