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"DNA methylation, hydroxymethylation and cancer"

Final 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. 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 focused on elucidating the biological function of a novel protein family (the TET proteins), which had the potential to regulated DNA methylation, and where one of the genes (TET2) had been found to be mutated with high frequency in hematological cancers.
To understand the role of the TET proteins in normal development, and how their loss of function can lead to leukemia, we have developed several different mouse models for acute myeloid leukemia, which is dependent on Tet2 loss and closely recapitulates gene expression profiles and hallmarks of human AMLs. By using these models, we have shown that Tet2 is specifically required for protecting specific regulatory elements (enhancers) from DNA methylation to prevent leukemic transformation. Furthermore, we have shown 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 to control DNA methylation fidelity. We have used the AML mouse models to identify potential targets for the development of new therapies for AML patients, and we hope that our current work will further qualify them for clincial use.
To get a better understanding of how TET2 activity is regulated and how the proteins is recruited to DNA, several experimental approaches have been undertaken. This has for instance led to the identification of O-Linked-N-acetylglucosamine Transferase, OGT as a TET2-binding protein 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. In the coming years, we expect many new discoveries started by this ERC project that will have an impact on understanding how DNA methylation affects normal development and how its deregulation can lead to cancer.