Epigenetic regulation occurs through a myriad of physical and chemical mechanisms that alter the structure and dynamics of chromatin.   The fundamental unit of eukaryotic chromatin is the nucleosome core particle, a protein/DNA complex that binds ∼147 base pairs of DNA around a histone octamer.  The nucleosome’s stability, and therefore the accessibility of the DNA wrapped around it, can be modified through post-translational modification to histones, the replacement of canonical histones with variants, and the binding of additional proteins such as linker histones.  Here, I will discuss efforts in our group to understand the physical basis of these processes.  In particular, I will focus on results of all-atom molecular dynamics simulations of single and poly-nucleosomal arrays.  These simulations show that the highly dynamic histone “tails” have structures and conformations that are regulated by post-translational modifications as well as the nucleosome’s composition.  Variants of the H2A histone serve to either tighten or loosen the nucleosome core, which decrease or increase DNA accessibility and alters the strength of allosteric networks within the complex.  Finally, linker histones binding in “on-dyad” and “off-dyad’ locations have distinct effects on the structure and energetics of linker DNA, and their effects can propagate into poly-nucleosomal arrays. Together, these factors create a hierarchy of mechanisms that are utilized by cells to control their gene expression.

Using molecular simulations to understand the physical mechanisms underlying epigenetic regulation

ACS Spring 2022

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