Modulations of DNA Contacts by Linker Histones and Post-translational Modifications Determine the Mobility and Modifiability of Nucleosomal H3 Tails

Post-translational histone modifications and linker histone incorporation regulate chromatin structure and genome activity. How these systems interface on a molecular level is unclear. Using biochemistry and NMR spectroscopy, we deduced mechanistic insights into the modification behavior of N-terminal histone H3 tails in different nucleosomal contexts. We find that linker histones generally inhibit modifications of different H3 sites and reduce H3 tail dynamics in nucleosomes. These effects are caused by modulations of electrostatic interactions of H3 tails with linker DNA and largely depend on the C-terminal domains of linker histones. In agreement, linker histone occupancy and H3 tail modifications segregate on a genome-wide level. Charge-modulating modifications such as phosphorylation and acetylation weaken transient H3 tail-linker DNA interactions, increase H3 tail dynamics, and, concomitantly, enhance general modifiability. We propose that alterations of H3 tail-linker DNA interactions by linker histones and charge-modulating modifications execute basal control mechanisms of chromatin function. [Display omitted] •Post-translational modifications and H1 binding affect nucleosomal H3 tail dynamics•Transient, electrostatic contacts with nucleosomal DNA control H3 tail mobility•Pre-modifications that weaken DNA contacts facilitate subsequent H3 tail modification•H3 tail modifications and linker histone occupancy segregate on a genome-wide level Stützer et al. found that within nucleosomes, linker histones generally inhibit modification of different sites in core histone H3 and reduce H3 tail dynamics. The authors show that the effects are caused by modulation of electrostatic interactions of the H3 tail with linker DNA, which are also controlled by charge-modulating post-translational modifications.