DNA methylation and hydroxymethylation in hematologic differentiation and transformation

Abstract

Maintenance of balances of DNA methylation and demethylation plays fundamental roles in many biological processes. Aberrant DNA methylation-demethylation cycles is closely linked to the onset and progression of cancer. Proteins of the TET family are Fe(II)- and 2-oxoglutarate-dependent dioxygenases that catalyze iterative oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and subsequent oxidized derivatives. In addition to their roles as transient intermediate of DNA demethylation, these oxidized methylcytosines represent epigenetic marks that influence chromatin structure and gene expression. Loss of TET functions, which leads to marked disruption of DNA methylation and hydroxymethylation profiles, is commonly observed in a wide range of cancers. Particularly, TET loss-of-function is strongly associated with hematologic malignancies of lymphoid and myeloid origin as well as diverse solid cancers. In this talk, I will present our recent findings on the role of TET proteins in normal and malignant hematopoietic development, with an emphasis on the previously unappreciated functions of TET proteins in controlling genome-wide DNA methylation patterns, cell lineage commitment and genome integrity during hematopoiesis. Understanding of the impact of TET dysregulation during oncogenesis and identification of ways to manipulate TET activity in cancer cells may provide new avenues to develop novel epigenetic therapy applicable to a wide range of cancers.