The World of SET‐Containing Lysine Methyltransferases

Abstract

Genomic DNA (deoxyribonucleic acid) in eukaryotic cells is compacted into chromatin that plays an important role in regulation of DNA replication, gene expression, recombination and repair. Chromatin is composed of nucleosomes – genomic DNA – wrapped around two copies of each of the four canonical histones: H2A, H2B, H3 and H4. The amino‐terminal tails of histones undergo multiple post‐translational modifications such as methylation, acetylation, phosphorylation, ADP (adenosine diphosphate)‐ribosylation and ubiquitination, resulting in chromatin remodeling. Lysine methylation of histones is a post‐translational modification playing a key role in regulation of gene expression and chromatin functioning. Each type of histones undergoes methylation at various lysines by SET domain‐containing methyltransferases (KMTs). These modifications act in a combinatorial or sequential manner with other histone modifications conforming to the ‘histone code’ hypothesis. Such interplay between histone modifications determines unique functional consequences for gene expression, DNA replication and mitosis. Importantly, KMTs are also able to methylate non‐histone targets, for example, important transcription factors, TP53, E2F1 and others, affecting their protein stability and activity.

Key Concepts

  • The amino‐terminal tails of histones undergo multiple post‐translational modifications. In particular, methylation of lysines in histones is a post‐translational modification regulating gene expression, chromatin remodeling, DNA methylation and non‐histone protein function.
  • Each type of histones undergoes methylation by SET lysine methyltransferases at various sites: Lys26, Lys121, Lys129, Lys159, Lys171, Lys177 and Lys192 in histone H1B; Lys5, Lys13 and Lys15 in histone H2A; Lys15 in histone H2B; Lys4, Lys9, Lys27, Lys36 and Lys79 in histone H3; and Lys20 and Lys59 in histone H4.
  • Different extent of methylation on multiple lysines within histones is associated with various transcriptional outcomes ranging from activation to complete repression of genes.
  • Different numbers of methyl groups on target lysines are recognised by special protein domains within transcription‐related proteins, which facilitate the formation of protein complexes on chromatin.
  • Defects in SET methyltransferases enzymes can lead to cancer, neurological disorders, growth and developmental defects and other human pathologies.

Keywords: methyltransferases; methylation; KMTs; histone modification; nucleosomes; post‐translational modifications

Figure 1. Post‐translational modifications of the histones H1B, H2A, H2B, H3 and H4 tails. These modifications include methylation (red), acetylation (green), phosphorylation (blue) and ubiquitination (orange).
Figure 2. Taxonomic distribution of proteins containing SET domain (according to SMART database).
Figure 3. Structures of SET domain MLL methyltransferase, PHD, chromo, 3‐MBT and ankyrin repeats (a). Human MLL1 in ternary complex with H3 peptide and AdoHcy [Protein Data Bank (PDB) code 2W5Z]; (b) PHD domain from TAF3 in complex with a H3K4me3 peptide (PDB code 2K17); (c) HP1 chromo domain in complex with H3K9me2 peptide (PDB code 1KNA); (d) 3‐MBT from L3MBTL1 in complex with H1.5K27me2 (PDB code 2HRI); (e) ankyrin repeat domain from GLP in complex with Kme (PDB code 3B95).The post‐SET, SET domains in MLL1, PHD in TAF3, chromo in HP1, 3‐MBT in L3MBTL1 and ankyrin repeats in GLP are indicated.
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Vasileva, Elena, and Barlev, Nickolai(Jan 2017) The World of SET‐Containing Lysine Methyltransferases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026791]