Histones: at the crossroads of peptide and protein chemistry.

Abstract

In eukaryotic cells, inheritable information is stored in a nucleoprotein complex referred to as chromatin.1 This genome architecture serves two key purposes. On the one hand, wrapping DNA (approximately 145–147 basepairs) twice around a spool composed of two copies each of the highly basic core histones H2A, H2B, H3, and H4 leads to compaction of DNA strands (Figure ​(Figure1a,b).1a,b). These assemblies are called nucleosomes. Contacts between individual nucleosomes are often mediated by cationic tails at the N- and C-termini of all histone proteins that protrude from the core and further tighten the chromatin fiber (Figure ​(Figure1c).1c). Additional packing is achieved through attachment of histone H1 to the DNA that links neighboring nucleosomes or by nonhistone proteins that are able to bridge units within or between chromatin fibers.2 The second pivotal function of storing genetic information as a DNA–protein complex is the additional layer of regulation that this feature provides.3−5 For instance, the very presence of histones on DNA sequences can occlude access to these sites by transcription factors and other DNA binding proteins.6 Thus, nucleosome positioning, shaped in part by DNA sequence preferences and shifted by ATP-powered molecular motors (referred to as chromatin remodelers), directly affects chromatin transactions.7 Beyond their location, the biochemical makeup of nucleosomes provides further opportunity for regulation. Canonical histones can be replaced with closely resembling variants, and all histones are dynamically decorated with post-translational modifications (PTMs). These biochemical marks can be as small as just a few atoms, such as methyl (Lys, Arg, Gln), acetyl (Lys), or phosphoryl groups (Ser, Thr), or as large as an entire protein in the case of ubiquitin or SUMO. Upon attachment by dedicated transferase enzymes, PTMs can directly alter the biophysical properties of the target protein, provide a docking site for specific interaction partners, interfere with binding events of other factors, or act through a combination of these mechanisms. In this way, signaling through histone PTMs serves to orchestrate chromatin-templated processes, including fine-tuning transcriptional outputs. Remarkably, transcriptional states can be inherited through cell division cycles, thus providing a mode of epigenetic memory.8,9 Not surprisingly, misregulation of the inputs and outputs of chromatin signaling occurs in many diseases, especially cancer.10−13 Figure 1 Chromatin architecture in eukaryotic cells. (a) Structure of a mononucleosome. DNA (gray) is wrapped around two copies each of H2A (orange), H2B (red), H3 (blue), and H4 (green); pdb code: 1kx5. (b) Electrostatic surface rendering of a histone octamer. ...