Correlating histone acetylation with nucleosome core particle dynamics and function

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 15; p. e2301063120
• Main Authors: Kim, Tae Hun, Nosella, Michael L, Bolik-Coulon, Nicolas, Harkness, Robert W, Huang, Shuya Kate, Kay, Lewis E
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11-04-2023
• Subjects: Acetylation; Biological Sciences; Chromatin; Core particles; Deoxyribonucleic acid; DNA; Dynamic structural analysis; Epigenetics; Genetic code; Histones; Histones - metabolism; Light scattering; Lysine; Lysine - metabolism; Magnetic resonance spectroscopy; Molecular dynamics; NMR; NMR spectroscopy; Nuclear magnetic resonance; Nuclease; Nucleosomes; Photon correlation spectroscopy; Protein Processing, Post-Translational; Proteins; Thermodynamic models; conformational heterogeneity; nucleosomal DNA ligation and degradation; nucleosome structural dynamics; methyl-TROSY NMR
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2301063120

Epigenetic modifications of chromatin play a critical role in regulating the fidelity of the genetic code and in controlling the translation of genetic information into the protein components of the cell. One key posttranslational modification is acetylation of histone lysine residues. Molecular dynamics simulations, and to a smaller extent experiment, have established that lysine acetylation increases the dynamics of histone tails. However, a systematic, atomic resolution experimental investigation of how this epigenetic mark, focusing on one histone at a time, influences the structural dynamics of the nucleosome beyond the tails, and how this translates into accessibility of protein factors such as ligases and nucleases, has yet to be performed. Herein, using NMR spectroscopy of nucleosome core particles (NCPs), we evaluate the effects of acetylation of each histone on tail and core dynamics. We show that for histones H2B, H3, and H4, the histone core particle dynamics are little changed, even though the tails have increased amplitude motions. In contrast, significant increases to H2A dynamics are observed upon acetylation of this histone, with the docking domain and L1 loop particularly affected, correlating with increased susceptibility of NCPs to nuclease digestion and more robust ligation of nicked DNA. Dynamic light scattering experiments establish that acetylation decreases inter-NCP interactions in a histone-dependent manner and facilitates the development of a thermodynamic model for NCP stacking. Our data show that different acetylation patterns result in nuanced changes to NCP dynamics, modulating interactions with other protein factors, and ultimately controlling biological output.