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...

Cells employ elaborate mechanisms to introduce structural and chemical variation into chromatin. Here, we focus on one such element of variation: methylation of lysine 4 in histone H3 (H3K4). We assess a growing body of literature, including treatment of how the mark is established, the patterns of methylation, and the functional consequences of this epigenetic signature. We discuss structural aspects of the H3K4 methyl recognition by the downstream effectors and propose a distinction between sequence-specific recruitment mechanisms and stabilization on chromatin through methyl-lysine recognition. Finally, we hypothesize how the unique properties of the polyvalent chromatin fiber and associated effectors may amplify small differences in methyl-lysine recognition, simultaneously allowing for a dynamic chromatin architecture.

Various chemical modifications on histones and regions of associated DNA play crucial roles in genome management by binding specific factors that, in turn, serve to alter the structural properties of chromatin. These so-called effector proteins have typically been studied with the biochemist's paring knife -the capacity to recognize specific chromatin modifications has been mapped to an increasing number of domains that frequently appear in the nuclear subset of the proteome, often present in large, multisubunit complexes that bristle with modification-dependent binding potential. We propose that multivalent interactions on a single histone tail and beyond may have a significant, if not dominant, role in chromatin transactions.The eukaryotic genome is assembled into chromatin, and the nucleosome serves as its fundamental organizational unit. This unit is composed of an octamer of core histone proteins (two copies of H2A, H2B, H3 and H4) encircled by ∼146 bp of DNA. Histones project unstructured N-terminal 'tails' from the α-helical protein core of the nucleosome through the superhelical turns of DNA that enshroud the radial surface of the histone octamer. The majority of known histone post-translational modifications (PTMs) localize to residues in the unstructured tails, particularly at the N termini, yet a burgeoning number of modifications also appear to reside within the helical secondary structure and loops of folded histones 1 . Further diversifying the nucleosome core particle is a set of histone isoforms known as histone variants, some of which appear to have essential roles in various stages of DNA management [2][3][4][5] .The lowest order of chromatin structure is the nucleosomal unit iterated in extended conformation to resemble 'beads on a string', which can be consolidated into higher-order structures through the intermediacy of attendant proteins, RNA and cations. Physiological chromatin structure is a vital arbiter of DNA function, in that structural variation appears to regulate the accessibility of underlying DNA, ranging from condensed heterochromatin to more 'open' euchromatin 6,7 . Rather than mere static packaging of the genome, the spatial arrangement of chromatin serves as an information carrier that may help to preserve cell Correspondence to C.D.A., D.J.P and A.J.R. alliscd@rockefeller.edu, pateld@mskcc.org, aruthenbur@rockefeller.edu. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript identity through mitotic division 8 , and yet the local structure is sufficiently dynamic that it may be rapidly modulated by signalling cascades in response to external stimuli 9-11 .Phenotypic traits that are not encoded in the Watson-Crick base pairing of the genome are collectively referred to as epigenetic phenomena and appear to manifest physically as the faithful heritability of chromatin states by daughter cells [12][13][14] . The precise mechanisms of epigenetic phenomena are poorly understood, but causal connections between chemical modifications to DN...

Histone H3 Lys4 (H3K4) methylation is a prevalent mark associated with transcription activation. A common feature of several H3K4 methyltransferase complexes is the presence of three structural components (RbBP5, Ash2L and WDR5) and a catalytic subunit containing a SET domain. Here we report the first biochemical reconstitution of a functional four-component mixed-lineage leukemia protein-1 (MLL1) core complex. This reconstitution, combined with in vivo assays, allows direct analysis of the contribution of each component to MLL1 enzymatic activity and their roles in transcriptional regulation. Moreover, taking clues from a crystal structure analysis, we demonstrate that WDR5 mediates interactions of the MLL1 catalytic unit both with the common structural platform and with the histone substrate. Mechanistic insights gained from this study can be generalized to the whole family of SET1-like histone methyltransferases in mammals.