Reading, writing and editing methylated lysines on histone tails: new insights from recent structural studies

https://doi.org/10.1016/j.sbi.2010.09.012Get rights and content

The phenotypes of different cell types are governed by their differential gene expression programmes, which are prominently influenced by epigenetic gene regulation featuring heritable chromatin states. Different epigenetic states are associated with distinctive patterns of post-translational modifications of the histone tails, which in turn influence the recruitment of chromatin-modifying effectors and local chromatin structure. Despite rapid advances in understanding how particular histone marks correlate with transcriptional output, many of the molecular details on how the maintenance and alteration of these modifications relate to fundamental processes such as replication, DNA repair, and transcription remain to be elucidated. Here, we review recent advances in the structural description of the reading, writing, and editing of two histone methylation marks with opposite functions: at histone H3 lysine 4 (H3K4)—associated with actively transcribed genes, and at histone H3 lysine 27 (H3K27)—a hallmark of silenced chromatin. These two marks are associated with trithorax and polycomb, respectively, prototypes of the genes involved in epigenetic inheritance in Drosophila. We also briefly discuss some recent examples of how the readout of particular marks is influenced by the presence of other modifications.

Introduction

In eukaryotic cells, DNA is tightly packaged within the nucleus as chromatin. The basic building block of chromatin is the nucleosome, composed of 147 bp of DNA wrapped nearly twice around an octamer of eight core histones (two copies each of H3, H4, H2A, and H2B). The N-terminal tails of these core histones are unstructured and protrude outward from the nucleosome core and are subject to a range of reversible post-translational modifications, including acetylation, methylation, phosphorylation, ubiquitination and sumoylation. While some histone modifications can directly influence chromatin structure, many of them can be bound and ‘read’ by histone recognition modules found in many proteins and protein complexes that act on chromatin, often in a combinatorial fashion. It is now well established that many of the histone modifications are fundamental to the regulation of a diverse set of biological processes such as DNA replication, repair, recombination, and transcription. Some of the histone modifications can be copied and propagated through several cell divisions and thus contribute to epigenetic inheritance of transcriptional states [1, 2••].

The best-characterized histone modifications are lysine acetylation and methylation. Unlike acetylation, which is generally associated with active transcription, histone lysine methylation is associated with either active or repressed chromatin, depending on the context and extent (mono-, di-, and trimethylation) of this modification. This review will focus on the most recent structural advances and mechanistic insights in the regulation of two histone methylation marks: the methylation of lysine 4 and lysine 27 on histone H3, which are associated with active and repressed chromatin, respectively. Methylation of H3K4 and K27 are, respectively, the chromatin hallmarks of the trithorax and polycomb systems of Drosophila, among the best studied phenomena of epigenetic gene regulation involving histone modifications [3, 4]. We also review an instructive example of how combinatorial readout of histone tails bearing multiple modifications is achieved.

Section snippets

H3K4Me methylation

H3K4 methylation is a post-translational modification that is exclusively linked to transcriptional activation in a variety of eukaryotic species (see [5, 6, 7]). Recently, the role of H3K4 methylation in epigenetic inheritance of transcriptional states has been strengthened by a functional study in Dictyostelium [2••].

The first H3K4 methyltransferase to be identified was Saccharomyces cerevisiae Set1/KMT2, the only enzyme known to be responsible for mono-, di- and tri-methylaton of H3K4 in

H3K4 demethylation

Until recently, and unlike most other marks, histone methylation was thought to be an irreversible histone modification. This notion was attributed, in part, to the thermodynamic stability of the N–CH3 bond and to early studies demonstrating comparable turnover rates of bulk histones and the methyl groups on lysine and arginine residues on histones in mammalian cells [27, 28]. It was not until 2004 that Shi and colleagues [29] characterized the first histone demethylase, LSD1 (lysine-specific

H3K27me3

Trimethylation of H3K27 is associated with gene repression and silenced chromatin [37, 38, 39, 40]. Silencing through methylation of H3K27me3 is mediated by Polycomb group (PcG) proteins, which are present as three complexes: Polycomb repressive complex 1 (PRC1), PRC2 and PhoRC. Methylation of H3K27 is catalyzed by PRC2, and the H3K27me3 mark is read by PRC1 leading to silencing of target genes. In Drosophila, DNA-binding components of PhoRC and other DNA-binding proteins are thought to recruit

Reading and writing multiple modifications on a single histone tail

So far we have looked at how individual histone marks can be maintained. In reality, histones may carry many different marks. Conversely, many histone modifying enzymes (as well as nucleosome remodelling complexes) contain multiple histone recognition modules suggesting that they may read and write different histone modifications in a combinatorial fashion with possibilities for crosstalk and context-dependent editing of the histone marks (reviewed by [6]).

PHF8/KIAA1718

An interesting example of this has recently been published, which shows how the demethylation of H3K9 and H3K27 is differentially influenced by the presence of the H3K4me3 mark [60••].

PHF8 and KIAA1718 (also known as JHDM1D) are two related histone demethylases. Both enzymes contain a PHD finger that binds H3K4me3, and a catalytic JmjC domain. PHF8 demethylates H3K9me2 while KIAA1718 demethylates both H3K9me2 and H3K27me2. Horton et al. present structures of both enzymes and activity data with

Epilogue

The structural studies reviewed here demonstrate that reading, writing and editing of histone modifications involved in epigenetic gene regulation can be more intricate than originally anticipated: one histone modification can influence the reading or writing of another in many different ways. This may account for the existence of the large number of histone modifying enzymes and the many proteins decorated with a diverse array of histone recognition modules. Future structural studies of

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (60)

  • R.J. Klose et al.

    JmjC-domain-containing proteins and histone demethylation

    Nat Rev Genet

    (2006)
  • P. Stavropoulos et al.

    Crystal structure and mechanism of human lysine-specific demethylase-1

    Nat Struct Mol Biol

    (2006)
  • L.A. Boyer et al.

    Polycomb complexes repress developmental regulators in murine embryonic stem cells

    Nature

    (2006)
  • J. Muller et al.

    Histone methyltransferase activity of a Drosophila Polycomb group repressor complex

    Cell

    (2002)
  • J.J. Song et al.

    Structural basis of histone H4 recognition by p55

    Genes Dev

    (2008)
  • K.H. Hansen et al.

    A model for transmission of the H3K27me3 epigenetic mark

    Nat Cell Biol

    (2008)
  • P.V. Pena et al.

    Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2

    Nature

    (2006)
  • C.S. Ketel et al.

    Subunit contributions to histone methyltransferase activities of fly and worm polycomb group complexes

    Mol Cell Biol

    (2005)
  • J.R. Horton et al.

    Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases

    Nat Struct Mol Biol

    (2010)
  • G. Cavalli et al.

    Epigenetic inheritance of active chromatin after removal of the main transactivator

    Science

    (1999)
  • L. Ringrose et al.

    Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins

    Annu Rev Genet

    (2004)
  • J.A. Simon et al.

    Mechanisms of polycomb gene silencing: knowns and unknowns

    Nat Rev Mol Cell Biol

    (2009)
  • J.C. Eissenberg et al.

    Histone H3 lysine 4 (H3K4) methylation in development and differentiation

    Dev Biol

    (2010)
  • A. Shilatifard

    Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation

    Curr Opin Cell Biol

    (2008)
  • T. Miller et al.

    COMPASS: a complex of proteins associated with a trithorax-related SET domain protein

    Proc Natl Acad Sci USA

    (2001)
  • A. Roguev et al.

    The Saccharomyces cerevisiae Set1 complex includes an Ash2 homologue and methylates histone 3 lysine 4

    EMBO J

    (2001)
  • S. Glaser et al.

    Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development

    Development

    (2006)
  • M.G. Guenther et al.

    Global and Hox-specific roles for the MLL1 methyltransferase

    Proc Natl Acad Sci USA

    (2005)
  • B.D. Yu et al.

    Altered Hox expression and segmental identity in Mll-mutant mice

    Nature

    (1995)
  • M.S. Cosgrove et al.

    Mixed lineage leukemia: a structure–function perspective of the MLL1 protein

    FEBS J

    (2010)
  • Cited by (52)

    • Chromatin-bound RNA and the neurobiology of psychiatric disease

      2014, Neuroscience
      Citation Excerpt :

      Taken together, these clinical studies resonate nicely with the preclinical work in mice and further strengthen the notion that proper regulation of H3K4 methylation in immature cortical neurons is pivotal importance for neuronal health and function later in life. While the mono-methylated form of H3-lysine 27 is enriched in gene bodies of highly expressed genes in some tissues and cell types, including the erythroid system (Steiner et al., 2011), the di- and trimethylated forms are some of the best studied histone marks associated with gene silencing, repression and heterochromatization (Beck et al., 2010; Justin et al., 2010; Zhou et al., 2011). The H3K27-specific histone methyltransferase KMT6A, also known as Enhancer of zeste homolog 2 (EZH2), is associated with the polycomb repressive chromatin remodeling complex 2 (PRC2) (Herz and Shilatifard, 2010).

    • The future of neuroepigenetics in the human brain

      2014, Progress in Molecular Biology and Translational Science
      Citation Excerpt :

      Many active promoters, for example, are defined by high levels of histone H3 lysine 4 trimethylation in combination with various histone lysine acetylation markings, while repressive histone PTMs, including the trimethylated forms of H3K9, H3K27, and H4K20, potentially colocalize to some of the same loci in the genome and so forth.15 Proteins associated with the regulation of histone PTMs are sometimes referred to as “writers” or “erasers” or “readers,” essentially differentiating the process of establishing or removing a mark as opposed to its docking functions for chromatin remodeling complexes that regulate transcription or induce and maintain chromatin condensation.14,17,18 In addition to the core histones H2A/H2B/H3/H4, a number of histone variants, with H3.3, H3.1, H3.2, H2A.Z, and H2A.X, are some of the best-studied examples.

    View all citing articles on Scopus
    *

    These authors contributed equally to this work.

    On sabbatical leave.

    View full text