Cancer develops as a consequence of genetic and epigenetic changes and much evidence indicates that tumorspecific gain or loss of genomic DNA methylation may play a prominent role in both. However a clear picture has not yet emerged to explain the role(s) of methylation in neoplasia since both global hypomethylation as well as regional hypermethylation changes are found regularly in the same tumor. It is the aim of this proposal to determine which of these mechanisms operates in neoplasia arising in four different tissues and whether the methylation changes which are regularly seen in cancer are causallyrelated or are merely a consequence of other cellular insults that occur during the transformation process. Our approach involves the precise alteration of genomic DNA methylation levels by either inactivation or overexpression of the major mammalian DNA methyltransferases (MTases) Dnmtl and Dnmt3 in specific tissues of tumorprone mice. We will test the following four hypotheses which link DNA methylation and cancer each of which may be of selective advantage to the incipient tumor cell hypermethylation may cause (i) silencing of tumor suppressor genes and/or (ii) induce point mutations; hypomethylation may (iii) increase expression of oncogenes and/or (iv) cause genomic instability. Because methylation changes of genes leading to altered expression are in contrast to mutations reversible DNA MTases have become attractive drug targets for cancer treatment or prevention. Indeed previous results established that inhibition of Dnmtl either by genetic or pharmacological means can act synergistically in vivo to prevent intestinal tumor formation. However DNA MTase inhibitors are not without potential risks as inhibition of Dnmtl resulted in significantly higher somatic recombination (LOH) in ES cells and an increased lymphoma incidence in otherwise normal mice. Therefore information as to the potential benefits and risks of therapies which target DNA MTases is vital and our aim is to assess the consequences of methylation changes on tumor incidence in different tissues. The role of methylation in transcriptional regulation has not yet been defined although it is known to be essential for normal vertebrate development. To investigate a possible causal relation between methylation and gene control we will compare gene expression in matched cell lines where due to inducible Dnmtl deletion the genome is either normal or hypomethylated.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087869-02
Application #
6514705
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Okano, Paul
Project Start
2001-05-01
Project End
2006-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
2
Fiscal Year
2002
Total Cost
$645,180
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
076580745
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Sarkar, Sovan; Maetzel, Dorothea; Korolchuk, Viktor I et al. (2014) Restarting stalled autophagy a potential therapeutic approach for the lipid storage disorder, Niemann-Pick type C1 disease. Autophagy 10:1137-40
Sexton, Alec N; Regalado, Samuel G; Lai, Christine S et al. (2014) Genetic and molecular identification of three human TPP1 functions in telomerase action: recruitment, activation, and homeostasis set point regulation. Genes Dev 28:1885-99
Forster, Ryan; Chiba, Kunitoshi; Schaeffer, Lorian et al. (2014) Human intestinal tissue with adult stem cell properties derived from pluripotent stem cells. Stem Cell Reports 2:838-52
Torikai, Hiroki; Reik, Andreas; Soldner, Frank et al. (2013) Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122:1341-9
Buganim, Yosef; Faddah, Dina A; Jaenisch, Rudolf (2013) Mechanisms and models of somatic cell reprogramming. Nat Rev Genet 14:427-39
Dougan, Stephanie K; Dougan, Michael; Kim, Jun et al. (2013) Transnuclear TRP1-specific CD8 T cells with high or low affinity TCRs show equivalent antitumor activity. Cancer Immunol Res 1:99-111
Sarkar, Sovan; Carroll, Bernadette; Buganim, Yosef et al. (2013) Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease. Cell Rep 5:1302-15
Dawlaty, Meelad M; Ganz, Kibibi; Powell, Benjamin E et al. (2011) Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 9:166-75
Pawlak, Mathias; Jaenisch, Rudolf (2011) De novo DNA methylation by Dnmt3a and Dnmt3b is dispensable for nuclear reprogramming of somatic cells to a pluripotent state. Genes Dev 25:1035-40
Steine, Eveline J; Ehrich, Mathias; Bell, George W et al. (2011) Genes methylated by DNA methyltransferase 3b are similar in mouse intestine and human colon cancer. J Clin Invest 121:1748-52

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