Operating on chromatin, a colorful language where context matters

Abstract

Histones, the fundamental packaging elements of eukaryotic DNA, are highly decorated with a diverse set of post-translational modifications (PTMs) that are recognized to govern the structure and function of chromatin. Ten years ago, we put forward the histone code hypothesis, which provided a model to explain how single and/or combinatorial PTMs on histones regulate the diverse activities associated with chromatin (e.g., gene transcription). At that time, there was a limited understanding of both the number of PTMs that occur on histones and the proteins that place, remove, and interpret them. Since the conception of this hypothesis, the field has witnessed an unprecedented advance in our understanding of the enzymes that contribute to the establishment of histone PTMs, as well as the diverse effector proteins that bind them. While debate continues as to whether histone PTMs truly constitute a strict "code," it is becoming clear that PTMs on histone proteins function in elaborate combinations to regulate the many activities associated with chromatin. In this special issue, we celebrate the 50th anniversary of the landmark publication of the lac operon with a review that provides a current view of the histone code hypothesis, the lessons we have learned over the last decade, and the technologies that will drive our understanding of histone PTMs forward in the future.

Figure 1. Toolkit for modifying the chromatin template

Schematic illustrating the concept that writers place post-translational modifications on histone proteins (left), erasers remove such modifications from histone proteins (middle), and readers function to interpret these covalent modifications (right) to mediate diverse downstream processes.

Figure 2. Mechanisms of histone-recognition modules binding their target modification

Binding of specialized domains to histone post-translational modifications can occur in cis, where contact is made to a series of modifications on the same histone tail (A), or in trans, where contacts are made to distinct modifications across histone tails (B). Often, a single modification can serve as a docking site for more than one protein, in which secondary signals (e.g. other PTMs) may serve to dictate which protein is recruited to the specific mark (C). Proteins acting alone (A–B), or in the context of a macromolecular complex (D) can harbor multiple domains capable of facilitating chromatin recognition and binding. For clarity, no attempts have been made to depict histone recogntion between nucleosomes in either the same or distinct polynucleosome fibers, but these modes of binding recognition are also likely (reviewed in Ruthenburg et al. 2007).