Epigenetic modifications play an important role in chromatin remodeling. One typical example of these epigenetic modifications is DNA methylation. Methylation of DNA is mainly occurred at the 5 position of the cytosine pyrimidine ring in a CpG dinucleotide context, which is catalyzed by DNA methyltransferases. DNA methylation changes the status of chromatin and regulates numerous molecular cellular processes. Recently, TET family enzymes were shown to oxidize the methylated cytosine in a step towards DNA demethylation. These enzymes specifically convert methylated cytosine (5mC) mainly into hydroxymethylated cytosine (5hmC). Interestingly, unlike DNA demethylation, TET enzymes-dependent oxidation of methylated cytosine is not only associated with transcription activation but also transcription repression. It has been reported that TET1 forms a complex with SIN3A and HDAC1/2, which is involved in transcription repression. To study the molecular mechanism of TET enzyme-dependent DNA demethylation, we examined the associated proteins of TET enzymes using an unbiased protein affinity purification approach, and found OGT as a functional partner of TET2 in mouse ES cells. OGT is the only enzyme that uses UDP-GlcNAc as the donor to catalyze protein O-GlcNAcylation. Our preliminary study shows that OGT interacts with TET2 to form a heterodimer and is targeted to chromatin for histone GlcNAcylation via TET2 in mouse ES cells. Genome- wide profiling of TET2 and OGT suggests that TET2, OGT and OGT-dependent histone GlcNAcylation are associated with active gene transcription in mouse ES cells. Moreover, TET2 is one of the most frequently mutated genes in myeloid malignancies, suggesting that genetic mutations induce abnormal epigenetic modifications during carcinogenesis. Thus, in this application, we plan to examine the molecular mechanism of the TET2/OGT complex in epigenetic regulation as well as its role in tumorigenesis. The proposed study will reveal a novel mechanism of how somatic mutations deregulate several types of epigenetic modification, which may result tumorigenesis.

Public Health Relevance

The TET2/OGT complex plays an important role in epigenetic modifications during carcinogenesis. In particular, genetic mutations of TET2 gene are often associated with leukemogenesis. However, the molecular mechanism of the TET2/OGT complex remains elusive. In this proposal, we plan to examine: 1) The role of the TET2/OGT complex in DNA demethylation; 2) The role of the TET2/OGT complex in histone acetylation; 3) The functional defects of the genetic mutations of TET2 gene in cancers. The results are likely to reveal novel mechanisms of epigenetic modifications induced by genetic mutations during tumorigenesis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cancer Genetics Study Section (CG)
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Barski, Oleg
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Beckman Research Institute/City of Hope
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