Establishment, Erasure and Synthetic Reprogramming of DNA Methylation in Mammalian Cells

Abstract

DNA methylation is a crucial epigenetic modification involved in the control of cellular function and the balance between generation of DNA methylation and its removal is important for human health. This chapter focuses on the enzymatic machinery responsible for the processes of establishment, maintenance and removal of DNA methylation patterns in mammals. We describe the biochemical, structural and enzymatic properties of DNA methyltransferases and TET DNA hydroxylases, as well as their regulation in cells. We discuss how these enzymes are recruited to specific genomic loci, and how their chromatin interactions, as well as their intrinsic sequence specificities and molecular mechanisms contribute to the methylation pattern of the cell. Finally, we introduce the concept of epigenetic (re)programming, in which designer epigenetic editing tools consisting of a DNA targeting domain fused to an epigenetic editor domain can be used to edit the epigenetic state of a given locus in the genome in order to dissect the functional role of DNA methylation and demethylation. We discuss the promises of this emerging technology for studying epigenetic processes in cells and for engineering of cellular states.