Multivalent engagement of chromatin modifications by linked binding modules

Abstract

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...

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

“…Notably, our study highlights the functional versatility of these two conserved protein structural modules in chromatin-mediated transcriptional regulation. Some PHD fingers and bromodomains are known to act as methyllysine or acetyllysine binding domains, respectively, which can function either individually or sequentially in a tandem motif, as reported in BPTF 25,26 . Our study reveals a new functionality of the tandem PHD finger-bromodomain as one interactive functional unit in modulating gene transcription in a SUMOylation-dependent manner.…”

“…20,21) and Rsc4 of the yeast RSC remodeling complex 22 , the double chromodomain of Drosophila melanogaster CHD1 (chromo-ATPase/helicase-DNA binding) 23 and the double Tudor domain of JMJD2A 24 . However, although tandem modules of different structural folds such as the PHD finger and the bromodomain are found in many transcriptional proteins 25,26 , molecular mechanisms for their possible interactive functions are much less understood.…”

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.…”

Epigenetic Mechanisms in Stroke and Epilepsy

“…Nucleosomes are the basic unit of chromatin and are composed of 147 bp DNA wrapped around a histone octamer (two each of H2A, H2B, H3, H4), linker histone (H1) and histone variants (H2A.X, H2A.Z, H3.3) (Ruthenburg et al, 2007). Each histone has a central domain and unstructured N-terminal tails that contain multiple potential sites for post-translational modifications including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, and ADP ribosylation.…”

“…Each histone has a central domain and unstructured N-terminal tails that contain multiple potential sites for post-translational modifications including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, and ADP ribosylation. These marks are added or removed by a specific set of chromatin-modifying enzymes (Ruthenburg et al, 2007). Distinct, sitespecific histone modifications act sequentially or in combination to form a 'histone code' read by other proteins to bring about distinct downstream events, which in turn mediate active gene transcription or repression (Ruthenburg et al, 2007).…”