Reading, writing and editing methylated lysines on histone tails: new insights from recent structural studies
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
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2014, NeuroscienceCitation 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).
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2014, Progress in Molecular Biology and Translational ScienceCitation 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.