In the eukaryotic cell nucleus, the DNA is packaged in a structure called chromatin. The fundamental building block of chromatin is the nucleosome, which is composed of DNA wrapped around an octamer of four distinct histone proteins. Post-translational modifications (PTMs) of histone proteins can affect chromatin structure and function and thereby play critical roles in regulating gene expression. Most histone PTMs are found in unstructured histone tails that protrude from the nucleosome core. As a consequence, (synthetic) peptide truncations of these tails provide convenient substrates for the analysis of histone binding proteins and modifying enzymes. Modifications located on residues that reside in the nucleosome core are more difficult to study because short peptides do not recapitulate this defined structured state well. Methylation of histone H3 on Lys79 (H3K79), mediated by the Dot1 enzyme, is an example of such a core PTM. This modification, which is highly conserved, is linked to human leukemia, and pharmacological modulation of Dot1 activity could be a strategy to treat leukemia. Here we review the available and emerging genetic, biochemical, and chemical methods that together are starting to reveal the function and regulation of this and other histone modifications on the nucleosome core.
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