DNA methylation is essential for mammalian development and is a key epigenetic mechanism by which important developmental processes such as genomic imprinting and X chromosome inactivation are regulated. DNA methylation plays a crucial role in developmental regulation of gene expression, suppression of retrovirus infection and stable silencing of endogenous viruses. DNA methylation patterns are established during embryonic development and maintained in somatic tissues throughout adult life. Aberrant changes of DNA methylation patterns can lead to abnormal gene expression and diseases. In order to understand how DNA methylation patterns and thus gene expression profiles are regulated in normal development, it is important to study the enzymes that catalyze methylation and demethylation reactions. The identification of the Dnmt3 family of de novo methyltransferases opens many possibilities for experimental manipulation of this DNA modification system. This project will address a number of fundamental issues including the structure-function relationship of de novo methyltransferases Dnmt3a and 3b, the function of de novo methylation in cell proliferation, tissue differentiation, genomic imprinting and X inactivation, and the mechanism of transcriptional regulation of gene expression by DNA methylation. Genetic and biochemical approaches will be taken to investigate the functions of Dnmt3a and 3b in normal development and regulatory mechanisms of de novo methytransferase activities of Dnmt3a and 3b. Studies of Dnmt3a and 3b methyltransferases will provide new insights into epigenetic regulation of gene expression in development and will help understand how abnormal changes of DNA methylation patterns may cause diseases such as ICF syndrome and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM052106-06
Application #
6286991
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Carter, Anthony D
Project Start
1995-07-01
Project End
2004-11-30
Budget Start
2000-12-15
Budget End
2001-11-30
Support Year
6
Fiscal Year
2001
Total Cost
$322,815
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Ueda, Yoshihide; Okano, Masaki; Williams, Christine et al. (2006) Roles for Dnmt3b in mammalian development: a mouse model for the ICF syndrome. Development 133:1183-92
Dodge, Jonathan E; Okano, Masaki; Dick, Fred et al. (2005) Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J Biol Chem 280:17986-91
Sado, Takashi; Okano, Masaki; Li, En et al. (2004) De novo DNA methylation is dispensable for the initiation and propagation of X chromosome inactivation. Development 131:975-82
Dodge, Jonathan E; Kang, Yong-Kook; Beppu, Hideyuki et al. (2004) Histone H3-K9 methyltransferase ESET is essential for early development. Mol Cell Biol 24:2478-86
Chen, Taiping; Li, En (2004) Structure and function of eukaryotic DNA methyltransferases. Curr Top Dev Biol 60:55-89
Chen, Taiping; Tsujimoto, Naomi; Li, En (2004) The PWWP domain of Dnmt3a and Dnmt3b is required for directing DNA methylation to the major satellite repeats at pericentric heterochromatin. Mol Cell Biol 24:9048-58
Chen, Taiping; Ueda, Yoshihide; Dodge, Jonathan E et al. (2003) Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 23:5594-605
Gribnau, Joost; Hochedlinger, Konrad; Hata, Ken et al. (2003) Asynchronous replication timing of imprinted loci is independent of DNA methylation, but consistent with differential subnuclear localization. Genes Dev 17:759-73
Lehnertz, Bernhard; Ueda, Yoshihide; Derijck, Alwin A H A et al. (2003) Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 13:1192-200
Dodge, Jonathan E; Ramsahoye, Bernard H; Wo, Z Galen et al. (2002) De novo methylation of MMLV provirus in embryonic stem cells: CpG versus non-CpG methylation. Gene 289:41-8

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