How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers

Abstract

Histones comprise the major protein component of chromatin, the scaffold in which the eukaryotic genome is packaged, and are subject to many types of post-translational modifications (PTMs), especially on their flexible tails. These modifications may constitute a 'histone code' and could be used to manage epigenetic information that helps extend the genetic message beyond DNA sequences. This proposed code, read in part by histone PTM-binding 'effector' modules and their associated complexes, is predicted to define unique functional states of chromatin and/or regulate various chromatin-templated processes. A wealth of structural and functional data show how chromatin effector modules target their cognate covalent histone modifications. Here we summarize key features in molecular recognition of histone PTMs by a diverse family of 'reader pockets', highlighting specific readout mechanisms for individual marks, common themes and insights into the downstream functional consequences of the interactions. Changes in these interactions may have far-reaching implications for human biology and disease, notably cancer.The vast majority of DNA in eukaryotic organisms is intimately wrapped around core histone proteins, forming chromatin, the physiological context in which the genomes of these organisms must function. Control of the dynamics of chromatin structure has been implicated widely in regulating both access to and interpretation of the associated DNA template 1 . For example, numerous studies suggest that gene expression patterns can be positively or negatively regulated by complexes of proteins that fine-tune the structural properties of chromatin, often through covalent PTMs of histone proteins or other chromatin-remodeling complexes 2,3 . As chromatin architecture may be transmissible to daughter cells along a particular developmental lineage, histones and their PTMs are likely candidates for epigenetic information carriers that propagate phenotypic determinants not encoded in the DNA sequence. More than 70 different sites for histone PTMs and eight HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript types of histone PTMs have been reported, largely from the extensive application of mass spectrometry-and antibody-based detection techniques, as well as from metabolic-labeling studies [1][2][3] . Remarkably, almost two-thirds of potentially modifiable residues on histones have been characterized as PTM sites, and as more sensitive detection methods become available, this number is likely to increase. Despite the large number of histone PTMs, only a subset of amino acid residues in histones are known to be covalently modified, which include lysine (K), arginine (R), serine (S), threonine (T), tyrosine (Y), histidine (H) and glutamic acid (E) 1 . The majority of the PTMs are additions of relatively small yet chemically and structurally distinct moieties, such as acetyl, methyl and phosphate groups (Fig. 1a); these have been identified on sites ranging from the flexible tail...

The PHD domain of the sea urchin RAG2 homolog, SpRAG2L, recognizes dimethylated lysine 4 in histone H3 tails

“…1B) [ 28 ]. Interestingly, recent reports provide strong support for the idea that PHD domains, including those of RAG2, are amongst the recognition modules utilized by the cell to "read" the histone code in its nucleus by selectively binding to tails of histone H3 with distinct posttranscriptional modifications [reviewed in 20,21,34 ].…”

Epigenetic silencing of maspin expression occurs early in the conversion of keratocytes to fibroblasts

“…Methyl CpG binding proteins can bind methylated DNA and repress transcription (Bird and Wolffe, 1999;Yoon et al 2003;Kuzmichev et al 2004). In addition, specific modification of histones and binding of proteins that recognize these modifications can repress gene expression (Reviewed by Ruthenburg et al 2007 andTaverna et al 2007). The present study would predict that the rate of downregulation of maspin expression through these mechanisms is prolonged by the presence of FBS in the stromal cell cultures.…”

Epigenetics in the Human Brain

“…There are more than 100-amino acid residue-specific PTMs in a typical vertebrate cell (Tan et al, 2011), including mono (me1), di (me2)-, and tri (me3) methylation, acetylation and crotonylation, polyADP-ribosylation, and small protein (ubiquitin, SUMO) modification of specific lysine residues, as well as arginine (R) methylation and 'citrullination', serine (S) phosphorylation, tyrosine (T) hydroxylation, among others (Kouzarides, 2007;Tan et al, 2011;Taverna et al, 2007). These site-and residue-specific PTMs show close association with the functional architecture of chromatin, differentiating between promoters and gene bodies, enhancer and other regulatory sequences, condensed heterochromatin (Zhou et al, 2011) (Figure 1).…”