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The role of Tet2 protein in the 5-hydroxymethylcytosine enrichment of genomic DNA in stem cell-like phenotype in pre-malignant and pre-metastatic melanocytic lesions

Grant number: 12/25473-6
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2013
Effective date (End): November 30, 2013
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Miriam Galvonas Jasiulionis
Grantee:Guilherme Burgarelli Leite
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

During the malignant transformation of melanocytes, like other cellular types, DNA methylation patterns are found altered, affecting the genetic expression. A significative quantity of methylated cytosines (5mC) appears to be hydroxylated (5hmC) by 2-oxoglutarate and Fe(II) dependent dioxigenases, Tet1, 2 and 3 (Globish et al., 2010; Ko et al., 2010). There are evidences pointing 5hmC as a intermediary product in active DNA demethylation, which could contribute with DNA methylation dinamics. Furthermore, it was demonstrated that Tet1 and Tet2 are expressed in embrionic stem cell (Ito et al., 2010) and that 5hmC appears to play and important role in the maintenance and differentiation of these cells (Koh et al., 2011). However, the role of 5hmC and Tet proteins either in normal physiology or disease like cancer is not yet clear. In this project we intend to characterize alterations in Tet2 protein expression and 5-hydroxymethylcytosine levels in initial phases of melanoma progression in a murine in vitro melanocytic transformation model. Additionally, we will verify a possible association between these alterations and pluripotent characteristics observed in pre-malignant melanocytes and non-metastatic melanoma cells. The alterations of Tet2 and 5-hydroxymethycytosine leves will also be measured in human lineages of metastatic melanoma and tumoral specimens. This study will contribute to the understanding of the epigenetic regulatory mechanisms involving 5-hydroxymethylcytosine and Tet proteins in DNA methylation and characterization of useful biomarkers for risk prediction, diagnostic and prognostic, as well as possible therapeutic targets in melanoma.