Histone tails cooperate to control the breathing of genomic nucleosomes

Genomic DNA is packaged in chromatin, a dynamic fiber variable in size and compaction. In chromatin, repeating nucleosome units wrap 145-147 DNA basepairs around histone proteins. Genetic and epigenetic regulation of genes relies on structural transitions in chromatin which are driven by intra- and inter-nucleosome dynamics and modulated by chemical modifications of the unstructured terminal tails of histones. Here we demonstrate how the interplay between histone H3 and H2A tails control ample nucleosome breathing motions. We monitored large openings of two genomic nucleosomes, and only moderate breathing of an engineered nucleosome in atomistic molecular simulations amounting to 24 mu s. Transitions between open and closed nucleosome conformations were mediated by the displacement and changes in compaction of the two histone tails. These motions involved changes in the DNA interaction profiles of clusters of epigenetic regulatory aminoacids in the tails. Removing the histone tails resulted in a large increase of the amplitude of nucleosome breathing but did not change the sequence dependent pattern of the motions. Histone tail modulated nucleosome breathing is a key mechanism of chromatin dynamics with important implications for epigenetic regulation. Author summary In the cell, the DNA is packed in chromatin. Chromatin is a highly dynamic fiber structure made of arrays of nucleosomes with different degrees of compaction. Each nucleosome has 145-147 basepairs of DNA wrapped around a protein octamer made of four unique histone proteins. Each histone is present twice and has a structured part and one or two disordered terminal tails. The regulation of gene expression in the cell and during cellular transitions depends on dynamic changes in chromatin structure. Chromatin dynamics are modulated by intra and inter nucleosome motions and by posttranslational chemical modifications of the histone tails. Here we reveal how histone tails control the intra nucleosome dynamics at atomic resolution. From extensive sampling of nucleosome dynamics in atomistic molecular simulations, we show that genomic nucleosomes breath more extensively than engineered ones and we describe how two histone tails cooperate to control nucleosome breathing through interactions between clusters of positively charged residues and the DNA. Nucleosome conformations with different degrees of opening are associated with different conformations, positions, and DNA interaction patterns of the ta