Reading the Combinatorial Histone Language

Abstract

Histones are subject to frequent combinatorial post-translational modifications (PTMs), forming a complex chemical "language" that is interpreted by PTM-specific histone-interacting protein modules (reader domains). These specific interactions are thought to instruct gene expression and downstream biological functions. While the majority of studies have focused on individual modifications, our current understanding of the combinatorial PTM patterns on histones is starting to emerge, benefiting from the convergence of multiple technologies. Here, we review the key technical advances and progress on discovery and characterization of combinatorial histone PTM patterns. We focus on the interactions between reader domains and combinatorial PTMs, which is essential for understanding the mechanism and biological meaning of establishing and interpreting information embedded in histone PTM patterns.

Figure 1.. Post-translational modifications on histones recruit PTM-specific reader domains.

a. Nucleosome is the basic subunit in chromatin structure. Each nucleosome contains eight core histones, upon which post-translational modifications (PTMs, represented as lollipops and flags) take place. b. PTM states on lysine residue recruit specific reader domains. Unmodified lysine can be acetylated and methylated by corresponding enzymes. Specific reader domains can recognize different forms of lysine.

Figure 2.. Discovery of combinatorial histone PTM patterns.

a. Three modes of histone PTM combination. In the situation of two combinatorial PTMs, three modes are discussed here: (1) cis-histone where two modifications occur on the same histone molecule; (2) trans-histone (intranucleosome) where two modifications occur on two histone molecules within the same nucleosome; (3) trans-histone (internucleosome) where two modifications occur on two histone molecules from different nucleosomes. b. Convergence of different techniques (as illustrated by overlaps among circles, with each circle representing the corresponding technique) facilitates discovery and analysis of combinatorial histone PTMs.

Figure 3.. Interaction between reader domains and combinatorial histone PTMs.

a. Toolbox for constructing homogenous histone substrate bearing PTMs of interests with increasing complexity and throughput. b. Multi-site recognition of single reader domains with combinatorial histone PTM states (cis-histone). White circle represents the reader environment perceived by each reader domain. c. Three modes [(1) cis-histone, (2) trans-histone (intranucleosome) and (3) trans-histone (internucleosome)] of the multivalent interaction between tandem reader domains and combinatorial histone PTM states on histone substrates.

Figure 4.. Interplay between reader domains and the catalytic domains.

(a) A model of how reader-catalytic domain linkage yields dynamic PTM combinations. (b) Two modes (cis-histone and trans-histone) of catalytic activity guided by reader-histone interaction. (c) Interplay between reader domains and the catalytic domains in a multiprotein complex system.