Molecular Biology Commons^™

Characterizing The Role Of Thymine Dna Glycosylase In Transcriptional Regulation And Cancer In Vivo, Mohammad Haider Hassan

Electronic Thesis and Dissertation Repository

Cytosine methylation (5mC) is essential for transcriptional control and genomic stability and is often used as a prognostic marker in cancer. Although 5mC has long been considered a relatively stable epigenetic mark, recent studies have demonstrated that it can be reversed enzymatically by TET proteins which oxidize 5mC into 5-hydroxymethylcytosine (5-hmC), and then to 5-formylcytosine (5-fC) and 5-carboxylcytosine (5caC). This mechanism is known as active DNA demethylation and the base excision repair enzyme Thymine DNA Glycosylase (TDG) plays an essential role in this process by removing 5-fC and 5-caC which are subsequently replaced by the unmethylated cytosine. Importantly, homozygous loss …

The Role Of Thymine Dna Glycosylase (Tdg) And Dna Demethylation In Tgf Beta Signaling, Matthew E.R. Maitland

Electronic Thesis and Dissertation Repository

Prompted by findings that TGFβ stimulates thymine DNA glycosylase (TDG) dependent rapid DNA demethylation and activation of the CDKN2B gene, I investigated the global role of TDG and DNA demethylation in TGFβ signaling in HaCaT cells. Using dot blot analysis, I show that TGFβ treatment increases the global levels of 5-formylcytosine, an intermediate metabolite of active DNA demethylation. Characterization of genomic regions that undergo DNA demethylation and recruitment of TDG indicate that they are both frequent events, but only overlap at 11 genomic locations. I identified 440 TGFβ upregulated genes, 40 of which were bound by TDG and 169 that …

Transcriptional Regulation By The Oncogenic Znf217/Corest Complex, Gobi Thillainadesan

Electronic Thesis and Dissertation Repository

The ZNF217 transcription factor is an oncogene found within the 20q13 amplicon and is amplified and overexpressed in many cancers including breast and ovarian. Overexpression of ZNF217 leads to increased cell proliferation, survival, and causes resistance to TGFβ's anti-proliferative effects.

ZNF217 is a core constituent of a transcriptional complex that includes CoREST, HDAC1/2, LSD1, and the CtBP1/2. In this study, I have combined genome-wide biochemical approaches to identify genes directly regulated by ZNF217. I have identified the tumor suppressor and cell cycle inhibitor, p15^ink4b, as a direct target of the ZNF217 complex and demonstrated that ZNF217 represses the …