Abstract
Epigenetic regulation is critical for the precise control of cellular fate and developmental programs. Disruption of epigenetic information is increasingly appreciated as a potential driving mechanism in both developmental disorders as well as ubiquitous diseases such as cancer. Consistent with this, mutations in histone modifying enzymes are amongst the most frequent events in all of human cancer. While early studies have focused on the canonical enzymatic functions involved in catalyzing modifications to histones, more recent studies have uncovered a new layer of critical nonenzymatic roles in transcriptional regulation for these proteins. Here, we provide an overview of these surprising, yet exciting, noncanonical, noncatalytic roles, and highlight how these revelations may have important implications for understanding disease and the future of epigenome-targeting therapies.