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Mechanisms of TET2 DNA demethylase recruitment to specific genomic regions

Periodic Reporting for period 1 - TET2rec (Mechanisms of TET2 DNA demethylase recruitment to specific genomic regions)

Reporting period: 2018-03-01 to 2020-02-29

Acute myeloid leukemia (AML) patients frequently harbor mutations in the epigenetic modifier TET2, which is a DNA demethylase. DNA methylation is an epigenetic modification that occurs predominantly at CpG dinucleotides and have a major impact on transcription. Accordingly, it plays key roles in cellular identity specification, and, when deregulated, in cancer. The importance of DNA methylation in cancer is underscored by the clinical use of hypomethylating agents in the treatment of AML and other myeloid disorders. DNA methylation is a reversible process and, only recently, it was discovered that TET (Ten-eleven Translocation) proteins mediate DNA demethylation. Jawed vertebrates have three TET homologues (TET1, TET2 and TET3). All TET proteins contain a C-terminal catalytic region. Remarkably, while TET1 and TET3 share an N-terminal DNA binding domain (CXXC motif), TET2 has lost its CXXC motif during evolution. Therefore, it is not understood how TET2 binds DNA. The main goal of this project is to understand how TET2 binds to specific regions of the genome.
We have investigated the mechanisms of TET2 recruitment to DNA using different approaches including chromatin immunoprecipitation, RNA-sequencing and mass spectrometry. The hits identified hold great potential as TET2 interactors for future research. They can be used by scientists in academia to further elucidate the mechanism of TET2 function in health and disease.
Furthermore, the main researcher has acquired a deep knowledge of the hematology and epigenetics fields and expertise in a wide range of techniques. She has also improved her communication, teaching and science dissemination skills. Altogether, she has become a more mature and competitive scientist with an extended network of collaborators.