Grant

"DNA methylation, hydroxymethylation and cancer"

Funder: European Research Council

Dimensions: grant.3797938

Investigators

Affiliations

Organisations

  1. (1) University of Copenhagen, grid.5254.6, KU

Research Organisations

Countries

Denmark

Continents

Europe

Abstract

"DNA methylation patterns are frequently perturbed in human diseases such as imprinting disorders and cancer. In cancer increased aberrant DNA methylation is believed to work as a silencing mechanism for tumor suppressor genes such as INK4A, RB1 and MLH1. The high frequency of abnormal DNA methylation found in cancer might be due to the inactivation of a proofreading and/or fidelity system regulating the correct patterns of DNA methylation. Currently we have very limited knowledge about such mechanisms. In this research proposal, we will focus on elucidating the biological function of a novel protein family, which catalyzes the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl cytosine (5-hmC). By catalyzing this reaction the TET proteins most likely work as DNA demethylases, and they might therefore have a role in regulating DNA methylation fidelity. Interestingly, accumulated data has in the last 2 years shown that TET2 is one of the most frequently mutated genes in various hematological cancers. We propose to investigate the molecular mechanisms by which TET2 regulates normal hematopoiesis, how its inactivation leads to hematopoietic malignancies and how the protein contributes to the regulation of DNA methylation patterns and transcription. Furthermore, we propose several experimental approaches for identifying proteins required for the recruitment of TET proteins to target genes and to analyze their role in the regulation of DNA methylation patterns and in cancer. Finally, we will investigate the potential functional role of 5-hmC and explore the potential mechanisms by which this modification could be erased. We expect to provide new insights into the biology of DNA methylation, hydroxymethylation and contribute to unravel the roles of TET proteins in normal physiology and cancer."

Resulting publications

NORA University Profiles

University of Copenhagen

Funding information

Funding period: 2012-2017

Funding amount: EUR 2298000

Grant number: 294666

Research Categories

Main Subject Area

Fields of Research