Histones and histone modifications

Imagine trying to stuff about 10,000 miles of spaghetti inside a basketball. Then, if that was not difficult enough, attempt to find a unique one inch segment of pasta from the middle of this mess, or try to duplicate, untangle and separate individual strings to opposite ends. This simple analogy illustrates some of the daunting tasks associated with the transcription, repair and replication of the nearly 2 meters of DNA that is packaged into the confines of a tiny eukaryotic nucleus. The solution to each of these problems lies in the assembly of the eukaryotic genome into chromatin, a structural polymer that not only solves the basic packaging problem, but also provides a dynamic platform that controls all DNA-mediated processes within the nucleus. The basic unit of chromatin is the nucleosome core particle, which contains 147 bp of DNA wrapped nearly twice around an octamer of the core histones. The histone octamer is composed of a central heterotetramer of histones H3 and H4, flanked by two heterodimers of histones H2A and H2B. Each nucleosome is separated by 10–60 bp of ‘linker’ DNA, and the resulting nucleosomal array constitutes a chromatin fiber of ~10 nm in diameter. This simple ‘beads-ona-string’ arrangement is folded into more condensed, ~30 nm thick fibers that are stabilized by binding of a linker histone to each nucleosome core (note that linker histones are not related in sequence to the core histones). Such 30 nm fibers are then further condensed in vivo to form 100–400 nm thick interphase fibers or the more highly compacted metaphase chromosome structures. This organization of DNA into chromatin fibers hinders its accessibility to proteins that must ‘read’ and/or copy the nucleotide base sequence, and consequently such structures must be dynamic and capable of regulated unfolding–folding transitions. Each of the core histones has a related globular domain that mediates histone–histone interactions within the octamer, and that organizes the two wraps of nucleosomal DNA. Each histone also harbors an aminoterminal 20–35 residue segment that is rich in basic amino acids and extends from the surface of the nucleosome; histone H2A is unique in having an additional ~37 amino acid carboxy-terminal domain that protrudes from the nucleosome. These histone ‘tails’ do not contribute significantly to the structure of individual nucleosomes nor to their stability, but they do play an essential role in controlling the folding of nucleosomal arrays into higherorder structures. Indeed, in vitro removal of the histone tails results in nucleosomal arrays that cannot condense past the beads-on-astring 10 nm fiber. Although the highly basic histone tails are generally viewed as DNA-binding modules, their essential roles in tail-mediated chromatin folding also involve inter-nucleosomal histone–histone interactions.