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DNAMET Report Summary

Project ID: 294666
Funded under: FP7-IDEAS-ERC
Country: Denmark

Mid-Term Report Summary - DNAMET (DNA methylation, hydroxymethylation and cancer)

DNA methylation patterns are frequently perturbed in human diseases such as imprinting disorders and cancer. In cancer increased aberrant DNA methylation is believed to work as a silencing mechanism for tumor suppressor genes such as INK4A, RB1 and MLH1. The high frequency of abnormal DNA methylation found in cancer might be due to the inactivation of a proofreading and/or fidelity system regulating the correct patterns of DNA methylation. When this ERC funded project started, we had very limited knowledge about such mechanisms. We are focusing on elucidating the biological function of a novel protein family, which catalyzes the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl cytosine (5-hmC). By catalyzing this reaction the TET proteins most likely work as DNA demethylases, and they might therefore have a role in regulating DNA methylation fidelity. Interestingly, accumulated data has in the last 2 years shown that TET2 is one of the most frequently mutated genes in various hematological cancers.
We have developed a mouse model for acute myeloid leukemia, which is dependent on TET2 loss and closely recapitulates gene expression profiles and hallmarks of human AML1-ETO induced AML. Our results from using this model, which subsequently have been confirmed in human AML cells, suggest that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation, and that it is the combined silencing of several tumor suppressor genes in TET2-mutated hematopoietic cells that contribute to increased stem cell proliferation and leukemogenesis. In other words, TET2 appears both to have a direct regulatory role of specific genes and control DNA methylation fidelity. Currently we are using this and other AML models generated in the laboratory to identify potential targets for the development of new therapies for AML patients.
To understand the mechanism by which TET2 activity is regulated and how it is recruited to DNA, we have also taken several experimental approaches to identify TET2 candidate proteins. This has for instance led to the identification of O-Linked-N-acetylglucosamine Transferase, OGT and our results have provided a mechanism for how OGT is recruited to chromatin. The approach has also led us to focus on two proteins, CXXC4 and CXXC5 that both have the ability to bind special areas of the genome. We have shown that these proteins can bind to TET2, and have generated knockout mouse models to understand the role of these proteins in regulating TET2 activity, DNA methylation patterns and cancer development.
The project is running according to the plans. We have already provided insights into the mechanisms regulating DNA methylation patterns, and we expect that we in the next 2 years will provide more results that are important for understanding the biology of DNA methylation, hydroxymethylation and contribute to unravel the roles of TET proteins in normal physiology and cancer.

Reported by

Københavns Universitet
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