Binding of regulatory proteins to nucleosomes is modulated by dynamic histone tails

Abstract

Despite histone tails' critical roles in epigenetic regulation, little is known about mechanisms of how histone tails modulate the nucleosomal DNA solvent accessibility and recognition of nucleosomes by other macromolecules. Here we generate extensive atomic level conformational ensembles of histone tails in the context of the full human nucleosome, totaling 26 microseconds of molecular dynamics simulations. We explore the histone tail binding with the nucleosomal and linker DNA and observe rapid conformational transitions between bound and unbound states allowing us to estimate kinetic and thermodynamic properties of the histone tail-DNA interactions. Different histone types exhibit distinct, although conformationally heterogeneous, binding modes and each histone type occludes specific DNA regions from the solvent. Using a comprehensive set of experimental data on nucleosome structural complexes, we find that majority of the studied nucleosome-binding proteins and histone tails target mutually exclusive regions on nucleosomal or linker DNA around the super-helical locations ±1, ±2, and ±7. This finding is explained within the generalized competitive binding and tail displacement models of partners recruitment to nucleosomes. Finally, we demonstrate the crosstalk between different histone post-translational modifications, where charge-altering modifications and mutations typically suppress tail-DNA interactions and enhance histone tail dynamics.

Nucleosome conformation dictates the histone code

“…Taken together, our data indicates that nucleosome context strongly influences reader domain engagement with histone PTMs. Previous studies have noted reduced reader affinity on Nucs relative to histone tail peptides [23][24][25][26] , but here we show that the PTM(s) bound may also be restricted (e.g. loss of Nuc H4acetyl binding by the BPTF BD and PHD-BD tandem; Fig.…”

“…lysine demethylases / methyltransferases) show altered activity when comparing peptide and Nuc substrates [18][19][20][21][22] , suggesting the importance of the higher order environment. Similarly, several studies indicate that reader domains have altered affinity for histone tails in the Nuc context [23][24][25][26] .…”

Nucleosome composition regulates the histone H3 tail conformational ensemble and accessibility

“…Specifically, the standard TIP3P model used here may over-stabilize the tail/DNA interactions of each ensemble state and therefore suppress the localized dynamics on the ps-ns timescale. Indeed, this effect has recently been observed in the context of histone tail dynamics ( 76 , 77 ). Notably however, the tails are bound more weakly to the DNA and have greater solvent exposure upon loss of the dimer in these simulations in line with the NMR data.…”

The Yin and Yang of Histone Marks in Transcription

“…Acetylation of histone tails improves the efficiency with which RNAPII traverses chromatin in vitro, as does removing histone tails entirely (106). Modeling of histone tail conformations indicates that histone tails bind nucleosomal and linker DNA extensively, with longer residence times for H3 and H4 tails than for N-and C-terminal tails of H2A or H2B (99). Tails thus compete with nucleosome-binding proteins for contacts with DNA.…”