Structural and biochemical advances in mammalian DNA methylation

The control of transcription initiation in mammalian cells can be very broadly divided into three categories: intrinsic promoter strength and availability of core transcription machinery (Dvir et al. 2001, Sandelin 2007), the actions of promoter- or regulon-specific transcription factors (positive and negative) (e.g., (Malik and Roeder 2005, Hoffmann et al. 2006)), and the control of DNA accessibility by altering chromatin structure (Li et al. 2007, Berger 2007). This latter category, including posttranslational modifications to histones and postreplicational modification of DNA, is in many ways less well-understood than the other two. Nucleosomes are the fundamental building blocks of eukaryotic chromatin, and consist of ∼146 base pairs of DNA wrapped twice around a histone octamer (Luger et al. 1997). A variety of protein-modifying enzymes (including methyltransferases, MTases) is responsible for histone modification, primarily at their flexible N-termini (Shilatifard 2006, Shi 2007, Bhaumik 2007). We will touch on the functional links between histone modification and that of DNA, but the purpose of this chapter is to summarize, from a structural perspective, the rapidly-growing body of information about the proteins that methylate mammalian DNA.