Histone tail binding in the context of the nucleosome
The information content of every human cell is not only encoded in the genomic DNA sequence, but within histone proteins that, together, form chromatin. One of the most important questions in biology is how this information is read out by transcriptional and other regulatory complexes. Information in the histone proteins is largely encoded by post-translational modifications (PTMs), which are “read” through histone binding (or reader) domains within regulatory complexes. Though much is known about how individual reader domains associate with isolated histone fragments, very little is known about how histone modification states are read out in a chromatin relevant context. We propose that histone PTM function and cross-talk, as well as specific readout of the histone modification state by reader domains, can only be truly understood in the context of the nucleosome. We are pioneering the use of NMR spectroscopy to investigate reader/nucleosome complexes. We are working with several reader domains that harbor diverse histone binding properties, and provide excellent systems for us to test this hypothesis. I will discuss our recent results which demonstrate that; 1) the conformation of the histone tails in the context of the nucleosome can substantially alter readout of histone PTMs, 2) that histone PTM cross-talk may be mediated by nucleosome structure rather than simply combined readout, and 3) that several domains read out and respond to information in both the histone tails and DNA, leading to enhanced selectivity that can only be defined in the nucleosome context.