Abstract
Histone tails harbor a plethora of post-translational modifications that direct the function of chromatin regulators, which recognize them through effector domains. Effector domain/histone interactions have been broadly studied, but largely using peptide fragments of histone tails. Here, we extend these studies into the nucleosome context and find that the conformation adopted by the histone H3 tails is inhibitory to BPTF PHD finger binding. Using NMR spectroscopy and MD simulations, we show that the H3 tails interact robustly but dynamically with nucleosomal DNA, substantially reducing PHD finger association. Altering the electrostatics of the H3 tail via modification or mutation increases accessibility to the PHD finger, indicating that PTM crosstalk can regulate effector domain binding by altering nucleosome conformation. Together, our results demonstrate that the nucleosome context has a dramatic impact on signaling events at the histone tails, and highlights the importance of studying histone binding in the context of the nucleosome.
Highlights
Eukaryotic DNA is packaged into the cell nucleus in the form of chromatin
In order to determine how the context of the nucleosome may affect the association of PHD fingers with the histone H3 tail, we utilized nuclear magnetic resonance (NMR) spectroscopy to compare binding of the BPTF PHD finger to histone tail peptide and the nucleosome core particle (NCP)
Addition of a peptide corresponding to H3 residues 1–10 methylated at lysine 4 (H3(1–10)K4me3) (Figure 1A, left, and Figure 1—figure supplement 1A and 2C) to 15N-PHD resulted in extensive chemical shift perturbations (CSPs) in resonances for residues in the binding pocket (Figure 1C) as previously determined by NMR and crystallographic studies (Li et al, 2006)
Summary
Eukaryotic DNA is packaged into the cell nucleus in the form of chromatin This DNA/histone complex contributes to DNA compaction and restricts its accessibility, providing a mechanism for regulating the genome. The N-termini of all four histones, as well as the C-terminus of H2A, protrude to the exterior of the nucleosome core and are commonly referred to as histone tails. These tails can be extensively post-translationally modified, which is thought to be critical in regulation of chromatin structure.
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