Review
OPERating ON Chromatin, a Colorful Language where Context Matters

https://doi.org/10.1016/j.jmb.2011.01.040Get rights and content

Abstract

Histones, the fundamental packaging elements of eukaryotic DNA, are highly decorated with a diverse set of post-translational modifications (PTMs) that are recognized to govern the structure and function of chromatin. Ten years ago, we put forward the histone code hypothesis, which provided a model to explain how single and/or combinatorial PTMs on histones regulate the diverse activities associated with chromatin (e.g., gene transcription). At that time, there was a limited understanding of both the number of PTMs that occur on histones and the proteins that place, remove, and interpret them. Since the conception of this hypothesis, the field has witnessed an unprecedented advance in our understanding of the enzymes that contribute to the establishment of histone PTMs, as well as the diverse effector proteins that bind them. While debate continues as to whether histone PTMs truly constitute a strict “code,” it is becoming clear that PTMs on histone proteins function in elaborate combinations to regulate the many activities associated with chromatin. In this special issue, we celebrate the 50th anniversary of the landmark publication of the lac operon with a review that provides a current view of the histone code hypothesis, the lessons we have learned over the last decade, and the technologies that will drive our understanding of histone PTMs forward in the future.

Section snippets

The “histone code hypothesis”: the first 10 years

In 2000, we proposed what has come to be commonly referred to as the “histone code hypothesis,” which, in its original form, posits that “multiple histone modifications, acting in a combinatorial or sequential fashion on one or multiple histone tails, specify unique downstream functions.”15 Parallels to François Jacob's quote from “Evolution and Tinkering” are readily apparent. The same fixed set of amino acids that make up the histone proteins have the potential of being post-translationally

Transcribing the “histone code”: chicken or egg?

Although applicable to a diverse set of cellular processes, the histone code is most commonly considered in the context of transcription regulation. Within this realm, there has been much debate as to whether a putative code formed by combinatorial modifications can formally regulate transcription itself or, rather, if patterns of modifications are generally associated with a particular transcriptional state. On one side is the argument that genes are not necessarily regulated by chromatin

Tinkering the “histone code hypothesis” in years to come

The key question that remains then is perhaps not one of mulling over how to best define the histone code, but rather, what form will the histone code hypothesis take over the years to come? Given the rapidity of chromatin-based research and the prominent role of chromatin in numerous DNA-based processes, research in the years to come is likely to continue along the same fruitful path of discovery that it has witnessed in the past 10 years, demonstrating additional levels of complexity by which

Strict code versus rich language: exciting either way

At the time of inception, it is always difficult to discern how influential a hypothesis will truly be. We have been privileged to witness that François Jacob and Jacques Monod's report on the lac operon in the Journal of Molecular Biology in 1961 has revolutionized our understanding of the basic mechanisms underlying gene regulation. We are also beginning to understand the richness of the histone code hypothesis. When we posited this hypothesis, now 10 years ago, we had what in retrospect

Acknowledgements

We thank the many researchers whose studies have help to expand our understanding of both the lac operon and the histone code, and we apologize to those whose work could not be cited here due to space constraints. We also thank Nara Lee, Scott Rothbart, and the members of the Allis laboratory for insightful conversations and comments on the manuscript, and Nara Lee and Stephen Fuchs for assistance with the illustrations contained in this piece.

References (78)

  • PazinM.J. et al.

    What's up and down with histone deacetylation and transcription?

    Cell

    (1997)
  • VermeulenM. et al.

    Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4

    Cell

    (2007)
  • ZippoA. et al.

    Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation

    Cell

    (2009)
  • GarciaB.A. et al.

    Characterization of histones and their post-translational modifications by mass spectrometry

    Curr. Opin. Chem. Biol.

    (2007)
  • YoungN.L. et al.

    High throughput characterization of combinatorial histone codes

    Mol. Cell. Proteomics.

    (2009)
  • FuchsS.M. et al.

    Influence of combinatorial histone modifications on antibody and effector protein recognition

    Curr. Biol.

    (2011)
  • BarskiA. et al.

    High-resolution profiling of histone methylations in the human genome

    Cell

    (2007)
  • BernsteinB.E. et al.

    A bivalent chromatin structure marks key developmental genes in embryonic stem cells

    Cell

    (2006)
  • Kleine-KohlbrecherD. et al.

    A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation

    Mol. Cell.

    (2010)
  • VermeulenM. et al.

    Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers

    Cell

    (2010)
  • BartkeT. et al.

    Nucleosome-interacting proteins regulated by DNA and histone methylation

    Cell

    (2010)
  • GlozakM.A. et al.

    Acetylation and deacetylation of non-histone proteins

    Gene

    (2005)
  • HuangJ. et al.

    The emerging field of dynamic lysine methylation of non-histone proteins

    Curr. Opin. Genet. Dev.

    (2008)
  • JacobF.

    Evolution and tinkering

    Science

    (1977)
  • JacobF. et al.

    [Operon: a group of genes with the expression coordinated by an operator.]

    C R Hebd Seances Acad. Sci.

    (1960)
  • LugerK. et al.

    Crystal structure of the nucleosome core particle at 2.8 Å resolution

    Nature

    (1997)
  • KornbergR.D.

    Chromatin structure: a repeating unit of histones and DNA

    Science

    (1974)
  • WolffeA.P. et al.

    Chromatin disruption and modification

    Nucleic Acids Res.

    (1999)
  • BergerS.L.

    The complex language of chromatin regulation during transcription

    Nature

    (2007)
  • ClapierC.R. et al.

    The biology of chromatin remodeling complexes

    Annu. Rev. Biochem.

    (2009)
  • HoL. et al.

    Chromatin remodelling during development

    Nature

    (2010)
  • TalbertP.B. et al.

    Histone variants—ancient wrap artists of the epigenome

    Nat. Rev. Mol. Cell Biol.

    (2010)
  • StrahlB.D. et al.

    The language of covalent histone modifications

    Nature

    (2000)
  • SakabeK. et al.

    β-N-Acetylglucosamine (O-GlcNAc) is part of the histone code

    Proc. Natl Acad. Sci. USA

    (2010)
  • CollinsR.E. et al.

    The ankyrin repeats of G9a and GLP histone methyltransferases are mono- and dimethyllysine binding modules

    Nat. Struct. Mol. Biol.

    (2008)
  • TavernaS.D. et al.

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

    Nat. Struct. Mol. Biol.

    (2007)
  • VezzoliA. et al.

    Molecular basis of histone H3K36me3 recognition by the PWWP domain of Brpf1

    Nat. Struct. Mol. Biol.

    (2010)
  • LiuW. et al.

    PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression

    Nature

    (2010)
  • KellyA.E. et al.

    Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B

    Science

    (2010)
  • Cited by (286)

    • CRISPR, epigenetics, and cancer

      2023, Epigenetic Cancer Therapy, Second Edition
    View all citing articles on Scopus
    View full text