Regulation of Cellular Metabolism and Development by DNA Modifications
(i) DNA and histone modifications have a profound effect on both transcriptional regulation and cell fate. 5-hydroxymethylcytosine (5hmC) is a recently identified and stable DNA modification present in many types of mammalian cells. 5hmC is involved many processes – including the removal of 5-methylcytosine, transcriptional regulation, stem cell self renewal, stem cell differentiation, developmental abnormalities, and tumor formation. 5hmC results from the Tet1-3 enzyme catalyzed oxidation of 5-methylcytosine. As 5-methylcytosine is strongly linked to transcriptional regulation, it became clear that 5hmC might be involved in transcription. Our research strongly suggests that 5hmC is not only involved in transcriptional regulation but also involved in additional nucleic acid transactions.
I am working to expand my research into the field of Tet1-3 regulatory elements. Tet1-3 are relatively large proteins – between 179 and 235 kDa – with comparatively small catalytic domains. Their large size and small catalytic domains suggests that Tet1-3 enzymatic activity is regulated by other, undescribed proteins. Speculatively, this regulation would occur through interactions at the large regions on Tet1-3 that are not part of the catalytic domain. The current literature identifies or characterizes several proteins that interact with Tet1-3; however none of these proteins affects Tet1-3 activity. Screening for proteins that functionally interact with Tet1-3, we have identified several potential candidates. As aberrant 5hmC patterns are present in nearly all tumors and 5hmC is involved in an array of developmental processes, the results of this basic research will have wide ranging impacts in all these fields. Identification and characterization of Tet1-3 regulatory elements will strongly benefit both tumor biology and developmental biology.
(ii) My second research focus involves the development of a platform that will allow for the continuous directed evolution of DNA binding proteins in eukaryotic cells. Using state-of-the-art synthetic biology techniques, this method will allow us to create custom synthetic DNA binding proteins. As this technology allows us to create proteins that specifically recognize any DNA sequence, we envision that these synthetic proteins will have wide-ranging impacts in clinical diagnostics, molecular biology, and biochemical applications.
Adam Robertson, PhD (Group Leader), email@example.com, Oslo University Hospital , Department of Molecular Microbiology , Building B, 3rd floor, Room B2.3069 , Sognsvannsveien 20, NO-0027, Oslo, Norway
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