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The Acetylation Landscape of the H4 Histone Tail: Disentangling the Interplay between the Specific and Cumulative Effects
journal contribution
posted on 2015-05-20, 00:00 authored by David Winogradoff, Ignacia Echeverria, Davit A. Potoyan, Garegin A. PapoianHistone tails, the intrinsically
disordered terminal regions of
histone proteins, are key modulators of the structure and dynamics
of chromatin and, consequently, are central to many DNA template-directed
processes including replication, repair, and transcription. Acetylation
of histone tails is a major post-translational modification (PTM)
involved in regulating chromatin, yet it remains unclear how acetylation
modifies the disordered state of histone tails and affects their function.
We investigated the consequences of increasing acetylation on the
isolated H4 histone tail by characterizing the conformational ensembles
of unacetylated, mono-, di-, tri-, and tetra-acetylated H4 histone
tails using Replica Exchange Molecular Dynamics (REMD) simulations.
We found that progressive acetylation has a cumulative effect on the
H4 tail, decreasing conformational heterogeneity, increasing helical
propensity, and increasing hydrogen bond occupancies. The monoacetylation
of lysine 16, however, has unique and specific effects: drastically
decreasing the conformational heterogeneity of the H4 tail and leading
to highly localized helical secondary structure and elongated conformations.
We describe how the cumulative effects of acetylation arise from the
charge reduction and increased hydrophobicity associated with adding
acetyl groups, while the specific effects are a consequence of steric
interactions that are sequence specific. Additionally, we found that
increasing the level of acetylation results in the formation of spatially
clustered lysines that could serve as recognition patches for binding
of chromatin regulating proteins. Hence, we explore the mechanisms
by which different acetylation patterns may result in specific recognition
of the H4 histone tails by protein or DNA binding partners.