Histone post-translational modifications (PTMs) have numerous crucial roles in genome management, in part by recruiting or stabilizing chemical or structural modification activities. These recruited effector complexes are often composed of several domains that have been linked to modified histone recognition, and perform functions ranging from promoting transcription to establishing gene silencing.
We propose that multivalent interactions that are PTM dependent may act in concert to physically regulate chromatin structure and DNA-templated transactions. In principle, these cooperative binding interactions may yield enhanced net affinity, increased composite specificity and greater dynamics relative to similarly tight monovalent interactions.
We give a general description of chromatin marks that are known to coexist spatially and describe the experimental technologies used to establish these findings. Patterns of these modifications together may form substrates for multivalent recognition at the single-nucleosome level and beyond, which appear to dictate functional consequences.
The biophysics of multivalency has been well developed in other fields but is largely underappreciated and understudied in chromatin biology. We draw from the lessons learned in these other fields in describing how the thermodynamic principles of multivalency may explain several concerns about the histone code hypothesis. In particular, the weak affinities and often modest specificities intrinsic to a given histone-binding domain may be altered substantially when linked to a multivalent effector polypeptide or complex.
Although a well-characterized example that systematically describes multivalent effects on chromatin substrates is still lacking, we describe examples from the literature that are beginning to suggest the multivalent recognition theme. We hope to exhort further efforts to study this phenomenon and, to this end, propose a classification scheme to help clarify different putative modes of chromatin engagement.
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.
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We apologize to all authors whose important contributions could not be acknowledged due to space limitations. We thank members of the Patel and Allis laboratories for reading the manuscript and providing constructive criticism. We are especially grateful to H. Dormann, A. Goldberg, P. Lewis, S. Taverna, J. Wysocka and the anonymous reviewers. D.J.P. is supported by funds from the Abby Rockefeller Mauze Trust and the Dewitt Wallace and Maloris Foundations, and C.D.A. is supported by National Institutes of Health grants and funds from The Rockefeller University. A.J.R. is supported by an Irvington postdoctoral fellowship from the Cancer Research Institute.
A post-translational modification or chemical alteration of an amino acid residue (or residues) that occurs subsequent to its translation, introducing a new functional group into a given protein.
- Histone variant
An isoform of a particular histone type that is encoded as a distinct gene and denoted by an additional designation (for example, the bar body-deficient histone H2A gene product is called H2A.bbd). Some variants have specialized functions: notably, H2A.X is involved in DNA repair and H2A.Z is involved in gene regulation.
A highly condensed and transcriptionally less active form of chromatin that occurs at defined sites, such as centromeres, silencer DNA elements or telomeres.
Chromatin that appears to be less compact than condensed mitotic chromosomes. Active genes are contained within euchromatin.
- DNA methylation
A covalent modification of DNA at the 5-position of the cytosine nucleobase that is coupled to transcriptional repression. CpG sequence elements in gene regulatory regions are often modified in this manner to attenuate gene transcription.
- Direct nucleosome-intrinsic
A histone modification-dependent process that alters the physical properties of the nucleosome by modulation of interactions of the core histone octamer with DNA.
- Direct nucleosome-extrinsic
A histone modification-dependent process that alters the physical properties of chromatin by modulation of interactions between nucleosomes.
- Effector mediated
A chromatin modification-dependent process that changes or stabilizes the chromatin architecture through modification-dependent recruitment of accessory factors.
A protein domain that binds a particular histone modification to transduce a downstream function. Effector proteins themselves or other subunits of complexes in which they reside can be histone-modifying enzymes or chromatin-remodelling factors, or they can be involved in stabilization of heterochromatin or have some other gene regulatory role.
A domain with sequence conservation that is found in several transcriptional regulatory proteins involved in gene activation, and that has acetyl-Lys-binding activity.
- PHD finger domain
The plant homeodomain (PHD) zinc finger is found in many nuclear proteins that are thought to be involved in chromatin transactions.
Chromatin immunoprecipitation followed by amplification and microarray hybridization.
Chromatin immunoprecipitation followed by massively multiplexed sequencing.
- Lys acetylation
Acetylation of the ζ-amine of the Lys side chain, a PTM that is catalysed by histone acetyltransferases.
- Lys methylation
A PTM at the ζ-amine of Lys that adds one, two or three methyl groups.
- Arg methylation
A PTM of the η-nitrogens of Arg to introduce one or two methyl groups.
Binding enhancement caused by one or more discrete binding interactions that further assist such interactions, although not necessarily as a consequence of a conformational change.
The canonical methyl-Lys-binding protein fold that was initially characterized in HP1 and Polycomb proteins. A member of the Royal superfamily of folds.
- Negative cooperativity
Antagonism in binding that leads to sub-additive or repulsive binding energies.
- WD40 repeat
A protein motif that is composed of a 40-amino-acid repeat that forms a four-stranded antiparallel β-propeller sheet. WD40 proteins that contain 5–7 WD40 repeats may form β-propeller structures that participate in many cellular functions, including G-protein-mediated signal transduction, transcriptional regulation, RNA processing and regulation of vesicle metabolism.
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Ruthenburg, A., Li, H., Patel, D. et al. Multivalent engagement of chromatin modifications by linked binding modules. Nat Rev Mol Cell Biol 8, 983–994 (2007). https://doi.org/10.1038/nrm2298
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