Structural Biology of Epigenetic Targets: Exploiting Complexity

In the last two decades, epigenetic effectors have increasingly been shown to be major regulators of nuclear processes, with direct implications for cell homeostasis, response to external stimuli, development, and onset and progression of many diseases. This chapter focuses primarily on epigenetic macromolecular complexes from the various classes of epigenetic effectors whose structures have enlarged people's understanding of epigenetic mechanisms and paved the way for designing next-generation selective epi-drugs. Specifically, macromolecular interactions as well as mechanisms leading to structural rearrangements are described. In humans, DNA methylation occurs predominantly on cytosines in CpG motifs that often form clusters known as CpG islands. Protein arginine methyltransferases (PRMTs) are monomethylating and symmetrically or asymmetrically dimethylating arginine residues in histones and other cellular effectors. The stimulation-responsive motif (SRM) also makes direct interactions with the SET domain, suggesting an explanation for the allosteric activation of polycomb repressive complex 2 (PRC2) by the H3K27me3 epigenetic mark.