DNA methylation is a major epigenetic factor involved in gene regulation, genomic imprinting, and X-chromosome inactivation. Aberrant DNA methylation has been associated with several human mental retardation disorders including Rett, ICF, Fragile-X, and ATRX syndromes. However, little is known about how DNA methylation changes perturb neural function and lead to neurological disorders. The long-term objective of our research is to elucidate the role of DNA methylation in neural development and function. Using the conditional gene knockout approach, we have recently constructed a strain of mutant mice in which the maintenance methyltransferase gene Dnmtl is deleted exclusively in precursor cells of the central nervous system (CNS). Dnmtl deficiency in CNS precursor cells causes significant demethylation in differentiating neurons and glial cells. Mutant embryos carrying 95 percent of hypomethylated CNS cells die immediately after birth, indicating that hypomethylation disrupts vital CNS function for animal survival. In mosaic animals carrying 30 percent of Dnmtl-/- cells in the embryonic CNS, mutant cells are selectively eliminated during postnatal maturation, showing that methylation is also important for the survival of postnatal CNS cells. The goal of this proposal is to characterize the neural defects in the hypomethylated brain and define the molecular mechanism by which DNA hypomethylation influences the survival and differentiation of neurons and glia. Our working hypothesis is that DNA hypomethylation results in inappropriate expression of many neural genes, which subsequently leads to multiple defects during CNS development. We therefore propose the following Specific Aims: 1. To determine the effect of DNA hypomethylation on the cell fate determination of CNS precursor cells. 2. To determine whether DNA hypomethylation affects neuronal maturation and synaptic function. 3. To define the mechanism of cell death triggered by DNA hypomethylation in the postnatal CNS environment. The proposed study may provide fundamental insights into the role of DNA methylation in neural development as well as the disease mechanism underlying certain mental retardation disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044405-04
Application #
7056136
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Owens, David F
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2006
Total Cost
$349,922
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Dvash, Tamar; Fan, Guoping (2009) Epigenetic regulation of X-inactivation in human embryonic stem cells. Epigenetics 4:19-22
Fouse, Shaun D; Shen, Yin; Pellegrini, Matteo et al. (2008) 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 2:160-9
Shen, Yin; Matsuno, Youko; Fouse, Shaun D et al. (2008) X-inactivation in female human embryonic stem cells is in a nonrandom pattern and prone to epigenetic alterations. Proc Natl Acad Sci U S A 105:4709-14
Feng, Jian; Fouse, Shaun; Fan, Guoping (2007) Epigenetic regulation of neural gene expression and neuronal function. Pediatr Res 61:58R-63R
Shen, Yin; Chow, Janet; Wang, Zunde et al. (2006) Abnormal CpG island methylation occurs during in vitro differentiation of human embryonic stem cells. Hum Mol Genet 15:2623-35
Feng, Jian; Chang, Hua; Li, En et al. (2005) Dynamic expression of de novo DNA methyltransferases Dnmt3a and Dnmt3b in the central nervous system. J Neurosci Res 79:734-46
Fan, Guoping; Martinowich, Keri; Chin, Mark H et al. (2005) DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Development 132:3345-56
Golshani, Peyman; Hutnick, Leah; Schweizer, Felix et al. (2005) Conditional Dnmt1 deletion in dorsal forebrain disrupts development of somatosensory barrel cortex and thalamocortical long-term potentiation. Thalamus Relat Syst 3:227-233
Fan, Guoping; Hutnick, Leah (2005) Methyl-CpG binding proteins in the nervous system. Cell Res 15:255-61
He, Fei; Ge, Weihong; Martinowich, Keri et al. (2005) A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 8:616-25

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