Regulation of the H4 tail binding and folding landscapes via Lys-16 acetylation

Abstract

Intrinsically disordered proteins (IDP) are a broad class of proteins with relatively flat energy landscapes showing a high level of functional promiscuity, which are frequently regulated through posttranslational covalent modifications. Histone tails, which are the terminal segments of the histone proteins, are prominent IDPs that are implicated in a variety of signaling processes, which control chromatin organization and dynamics. Although a large body of work has been done on elucidating the roles of posttranslational modifications in functional regulation of IDPs, molecular mechanisms behind the observed behaviors are not fully understood. Using extensive atomistic molecular dynamics simulations, we found in this work that H4 tail mono-acetylation at LYS-16, which is a key covalent modification, induces a significant reorganization of the tail's conformational landscape, inducing partial ordering and enhancing the propensity for alpha-helical segments. Furthermore, our calculations of the potentials of mean force between the H4 tail and a DNA fragment indicate that contrary to the expectations based on simple electrostatic reasoning, the Lys-16 monoacetylated H4 tail binds to DNA stronger than the unacetylated protein. Based on these results, we propose a molecular mechanism for the way Lys-16 acetylation might lead to experimentally observed disruption of compact chromatin fibers.histone tails | atomistic simulations | polyelectrolytes

Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair

“…Acetylation of the H4 tails blocks this interaction and promotes unpacking of chromatin fibers (22)(23)(24)(25)(26). The acidic patch on the nucleosome surface is formed from a short stretch of acidic amino acids (the acidic domain) in the docking domain of H2A and H2A.Z ( Fig.…”

“…Thus, removal of H2A.Z-H2B dimers by Anp32e is likely coupled to the addition of new H2A-H2B dimers by other remodeling ATPases implicated in DSB repair, such as Ino80 (44,45). Further, because acetylation prevents the H4 tail from rebinding to the acidic patch (22)(23)(24)(25)(26), the combination of H2A.Z-H2B removal and H4Ac prevents interaction between nucleosomes and promotes the shift to open, flexible chromatin required for DSB repair (Fig. 6).…”

Chromatin fiber allostery and the epigenetic code

“…It is not only involved in recruiting specific histone tail-binding complexes, mainly bromodomains, as most epigenetic marks do. It has also a physical action: acetylation neutralizes the positive charges of the lysine residues, which in vitro eventually leads to disruption of compact chromatin fibers [52]. Therefore H4 tail acetylation is believed to activate transcription because it is related to increased DNA local accessibility within chromatin.…”

The physics of epigenetics

“…Potoyan & Papoian (Potoyan and Papoian, 2012) addressed the question of the decompaction induced by H4K16 acetylation, and carried out all-atom simulations in explicit solvent to compare the conformation of H4 tail with and without this modification. For the isolated histone tails, H4K16ac leads to slightly more compact and significantly more structured globular H4 tails.…”