We are working to understand the influence of core histone modifications on the structure and dynamics of nucleosomes and chromatin. There are over 100 known post-translational histone modifications (PTMs) that play important roles in gene expression as well as DNA replication and repair. The molecular functions of the majority of histone PTMs remain enigmatic. There are now over 100 PTMs that have been detected by mass spectrometry and are located within the nucleosome core and not readily accessible for protein binding. We hypothesized that these modifications directly alter the structure and dynamics of nucleosomes and chromatin to facilitate DNA processing. To investigate this hypothesis, we created nucleosomes and chromatin with eight separate post-translational modifications (Fig. 1). We then investigated and published on their influence on the structure and dynamics of nucleosomes and chromatin.
Fig. 1 Nucleosome structure (PMID: 1KX5) with the PTMs sites we have studied indicated by colored residues.
We have reported a number findings on how histone PTMs in the nucleosome core function. This includes the finding that that acetylation of H3 lysine 56 increases DNA accessibility by increasing the nucleosome unwrapping rate, and that phosphorylation of H3 threonine 118 converts nucleosomes into an altosome, a permanently altered nucleosome structure. Most recently, we reported in The Journal of Biological Chemistry that a combination of two histone PTMs can combine multiplicatively to increase DNA accessibility within the nucleosome by over an order of magnitude. This shows that PTM combinations can have a much larger influence on increasing accessibility than single PTMs. Greg Bowman and I published a 2014 review in Chemical Reviews on the impact of histone PTMs on chromatin dynamics. This review summarizes the work that a number of labs, including ours, has been done on this topic.