The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease

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. An abundance of recent findings suggest that, surprisingly, numerous epigenetic regulators also possess an array of critical noncatalytic roles in addition to their canonical histone modifying enzymatic activities.These functions range from the recruitment of other epigenetic modifiers and critical transcription factors to unexpected cytoplasmic functions and roles in three-dimensional genome organization, together offering extensive new insights into epigenome function and gene regulation.These discoveries reveal how the aberrant function of these epigenetic modifiers leads to profoundly altered transcriptional landscapes, ultimately disrupting developmental programs or driving carcinogenesis.Collectively, these mechanistic insights are providing exciting rationale for the testing of novel epigenome-targeting therapies in order to harness the tremendous potential of epigenetic therapy for human disease.