Modeling Distributive Histone Modification by Dot1 Methyltransferases: From Mechanism to Biological Insights

Methylation of histone proteins plays a crucial role controlling genome activity. To understand how the responsible histone methyltransferases are regulated it is important to know their fundamental biochemical properties within the cell and relate these to cellular methylation dynamics. Repeated experiment-modeling cycles have led to insights into the in vivo dynamics of methylation of lysine 79 on histone H3 (H3K79) by the methyltransferase Disruptor of Telomeric Silencing 1 (Dot1). Genetic perturbation in yeast, quantitative measurements, and computational modeling were combined to show that Dot1 employs an uncommon, distributive methylation mechanism. A steady-state in vivo methylation model using this information has provided validated explanations for methylation defects in mutants. Subsequent single-cell models have provided insights into the dynamics of H3K79 methylation throughout the cell cycle and uncovered a role for histone protein aging. These integrated modeling approaches will aid in understanding how regulatory mechanisms influence Dot1's role in gene expression, cell cycle progression, and cancer and can be applied to other methylation systems.