In mammalian DNA, 5-methylcytosine (5mC) is a minor base which plays a disproportionately critical role in development. DNA methylation is very dynamic during embryogenesis and is vital for parental imprinting, X inactivation, silencing of endogenous retroviruses, and the regulation of genomic stability. De novo methylation and demethylation also occur in somatic cells during differentiation, tumorigenesis, and aging. In contrast to the established relation between DNA methylation, DNA methyltransferases, and gene silencing, the enzymes and processes regulating DNA demethylation are not well understood.
In the Tahiliani Lab at NYU Langone, we discovered that TET1 catalyzes the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). We also found that 5hmC can be detected in the genome of mouse ES cells, and that both TET1 levels and 5hmC levels decline when ES cells are differentiated. These results suggest that 5hmC is a normal constituent of mammalian DNA, and identify TET1 as an enzyme with a potential role in epigenetic regulation through modification of 5mC. This study described a new class of enzymes that catalyze a new modification of DNA and alters our perception of how DNA methylation status may be regulated in cells.
The description of the regulated conversion of 5mC to 5hmC raises an enormous number of new questions that are of pressing importance. The goal of the Tahiliani Lab is to integrate 5hmC into known pathways of 5mC metabolism and to determine how 5hmC exerts its influence on the genome with the ultimate goal of understanding the role that 5mC and 5hmC play in genomic stability.
Mamta V. Tahiliani, PhD
Assistant Professor, Department of Biochemistry and Molecular Pharmacology
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