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  • Review Article
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Sound of silence: the properties and functions of repressive Lys methyltransferases

Key Points

  • Lys methyltransferases (KMTs) belong to a large protein family that is characterized by the presence of the conserved catalytic SET domain. By using S-adenosyl-l-Met as a methyl group donor, KMTs are able to mono-, di- or trimethylate Lys residues on histones and on non-histone substrates.

  • KMTs have additional motifs that confer the ability to recognize various post-translational modifications (PTMs) and catalyse the methylation of neighbouring Lys residues. Thus, KMTs propagate as well as establish Lys methylation marks.

  • KMTs that are involved in gene silencing are mainly those that catalyse the methylation of histone H3 Lys 9 (H3K9), H3K27 and H4K20. Such KMTs can also mediate gene silencing by targeting non-histone substrates, including sequence-specific transcription factors.

  • KMTs are targeted to the chromatin by various mechanisms, such as through sequence-specific transcription factors, chromatin-binding proteins and non-coding RNAs. Some of these interactions mediate the co-recruitment of different KMTs at common genomic loci.

  • KMTs induce gene repression through cooperation with histone demethylases (which erase activating methyl marks), deacetylases and other KMTs. This results in chromatin compaction and the localization of the targeted chromatin regions to silencing nuclear compartments such as Polycomb foci and the nuclear lamina.

  • KMTs are responsible for the maintenance of defined gene expression programmes and cellular states; for example, they are important regulators of embryonic and adult stem cell differentiation and reprogramming. Deregulation of KMTs is often linked with diseases, including cancers and neurological disorders.

Abstract

The methylation of histone Lys residues by Lys methyltransferases (KMTs) regulates chromatin organization and either activates or represses gene expression, depending on the residue that is targeted. KMTs are emerging as key components in several cellular processes, and their deregulation is often associated with pathogenesis. Here, we review the current knowledge on the main KMTs that are associated with gene silencing: namely, those responsible for methylating histone H3 Lys 9 (H3K9), H3K27 and H4K20. We discuss their biochemical properties and the various mechanisms by which they are targeted to the chromatin and regulate gene expression, as well as new data on the interplay between them and other chromatin modifiers.

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Figure 1: The domain composition and substrate specificities of the different repressive Lys methyltransferases.
Figure 2: Interdependency in the establishment and propagation of the different repressive histone Lys methylation marks.
Figure 3: Recruitment and crosstalk of Lys methyltransferase at target regions.
Figure 4: Crosstalk between repressive Lys methyltransferases and other chromatin modifiers in the regulation of gene expression.

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Acknowledgements

Work in A.-S.-A.'s laboratory was supported by the Association Française contre les Myopathies – Téléthon (AFM); Institut National du Cancer (INCa); Agence Nationale de la Recherche (ANR), Fondation Association pour la Recherche sur le Cancer (ARC); the ''Who Am I?'' Laboratory of Excellence #ANR-11-LABEX-0071 funded by the French government through its '“Investments for the Future'” programme operated by the ANR under grant #ANR-11-IDEX-0005-01; the Groupement des Entreprises Françaises pour la Lutte contre le Cancer (GEFLUC); CNRS and Université Paris Diderot. C.M. was a recipient of FRM and EMBO fellowships, E.B. was supported by grant INCa and J.P. was a recipient of a Ministère de la Recherche, Fondation ARC Ph.D. fellowship and a Transition postdoctoral 'Who am I?' fellowship, 2015.

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Correspondence to Chiara Mozzetta or Slimane Ait-Si-Ali.

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Supplementary information

Supplementary information S1 (box)

Non-histone substrates of Lys methyltransferases (PDF 144 kb)

Supplementary information S2 (table)

Known non-histone KMT substrates, described in supplementary information S1 (PDF 159 kb)

Supplementary information S3 (box)

Diseases associated with the misregulation of Lys methyltransferases (PDF 149 kb)

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FURTHER INFORMATION

InterPro

Glossary

Writer

An enzyme that catalyses the addition of chemical modifications to DNA or histones.

Eraser

An enzyme that catalyses the removal of chemical modifications from DNA or histones.

Reader

An effector protein that binds only to histones or DNA that have certain chemical modifications.

Pre-SET

The region at the amino-terminal side of the SET domain of most Lys methyltransferases, which stabilizes the SET domain.

Post-SET

Part of the active site of most Lys methyltransferases. It is located at the carboxy-terminal side of the SET domain and participates in binding to histone tails and interactions with cofactors.

Pericentromeric heterochromatin

Repeats of constitutive heterochromatin that flank the central kinetochore-forming region of the centromere and that are necessary for proper centromere function.

Tudor domains

Conserved structural motifs of approximately 60 amino acids, which were originally found in the Drosophila melanogaster Tudor protein. They bind to methylated Lys and Arg residues.

Constitutive heterochromatin

Highly compact chromatin at regions such as centromeres and telomeres, which are mostly transcriptionally inactive in all cell types.

Facultative heterochromatin

A dynamic subtype of heterochromatin that is formed from euchromatin in a cell type-dependent manner to consolidate the repression of genes.

Zinc-finger proteins

(ZFPs). DNA-binding proteins that contain the zinc-finger motif and recognize DNA in a sequence-specific manner. They are often found in complex with Lys methyltransferases and are likely to mediate their recruitment to specific loci.

Endogenous retroviruses

(ERVs). Relics of retroviruses that successfully colonized metazoan genomes. They constitute approximately 8% of the human genome and transpose through an RNA intermediate.

CpG islands

Genomic regions with high cytosine and guanine dinucleotide levels found in many mammalian promoters, where they are normally hypomethylated to allow gene expression.

Major satellite RNA

RNA that is transcribed from major satellite DNA repeats found at pericentromeric regions in mice.

Argonaute

Family of proteins that are essential components of RNA-induced silencing complexes, which, in conjugation with short interfering RNAs, target genes for silencing.

Transcriptional gene silencing

Silencing that is achieved by the formation of repressive chromatin modifications (DNA methylation and/or histone modifications) at a locus, through the targeting of non-coding RNA.

Antigene RNAs

(agRNAs). Small double-stranded RNAs that target gene promoters and mostly inhibit transcription by interacting with Argonaute proteins.

Krüppel-associated box

(KRAB). A domain found in a subgroup of zinc-finger proteins that mediates protein–protein interactions and represses transcription by recruiting co-repressors.

Long terminal repeats

(LTRs). Repeats at both ends of retrotransposons that allow transcription and polyadenylation of retrotransposon mRNAs and are required for retroviral insertion into the genome.

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Mozzetta, C., Boyarchuk, E., Pontis, J. et al. Sound of silence: the properties and functions of repressive Lys methyltransferases. Nat Rev Mol Cell Biol 16, 499–513 (2015). https://doi.org/10.1038/nrm4029

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