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Only very few enzymes are known to catalyze protein histidine methylation. Here, the authors show that METTL9 is responsible for most 1-methylhistidine modifications in mouse and human proteomes, and characterize METTL9′s substrate specificity and potential cellular functions.

KMT9, a new histone lysine methyltransferase targeting H4K12, is enriched at promoters of genes encoding molecules involved in the cell cycle and controls the growth of androgen receptor–dependent and castration- and enzalutamide-resistant prostate cancer cells and xenograft tumors.

In mammals, DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B. Here the authors report the crystal structures of DNMT3B in complex with both CpG and CpA DNA, providing insight into the substrate-recognition mechanism underpinning the divergent genomic methylation activities of DNMT3A and DNMT3B.

DNA methylation is one of the major epigenetic mechanisms that critically influence gene expression, genomic stability and cell differentiation. Here, the authors study DNMT1 in complex with DNA substrates and systematically analyze the mechanism and specificity of DNMT1.

Recording systems would allow synthetic organisms to store a ‘memory’ of a past event for future reference. Here the authors design an epigenetic memory system inE. colithat methylates DNA in response to exogenous and endogenous signals.

SETDB1 is a histone methyltransferase that generates H3K9me3 marks in euchromatic regions. Here the authors show that the triple Tudor domain (3TD) of SETDB1 binds histone H3 tails containing K14 acetylation combined with K9 methylation, and that the K9me–K14ac modification defines a novel chromatin state enriched at SETDB1 binding sites.

By recruiting the Dnmt1 DNA methyltransferase to hemimethylated DNA, the ubiquitin-like with PHD and ring finger domains 1 (UHRF1) protein plays an important part in DNA methylation. The structures of the SRA domain of UHRF1 in complex with hemimethylated DNA show that the methylated cytosine is flipped out of the DNA helix, as observed previously with DNA methyltransferases.

Tools for imaging epigenetic modifications can shed light on the regulation of epigenetic processes. Here, the authors present a fluorescence complementation approach for detection of DNA and histone methylation at endogenous genomic sites allowing following of dynamic changes of these marks by live-cell microscopy.

A crystal structure of a complex between the DNA methyltransferase regulatory factor Dnmt3L and the catalytic domain of Dnmt3a leads to a model being proposed for the preferential methylation of DNA on maternally imprinted genes.

N-degron pathways play an important role in maintaining protein homeostasis. Here, Li et al. demonstrates an additional non-Ac/N-degron pathway, in which N-terminal non-acetylated small residue degrons (Ser, Ala, or Cys) are recognized by CRL2^ZER1/ZYG11B and targeted for protein degradation.

DNA methylation is an essential epigenetic mark in mammals. The maintenance of this mark relies on two key proteins: DNMT1 and UHRF1. Here the authors show that, beyond activating DNMT1, UHRF1 has crucial regulatory functions in cancer cells.

Protein lysine methylation plays important biological roles but its experimental characterization is limited by the lack of suitable mimetics of methylated and unmethylated lysine among the natural amino acids. Here, we summarize the consequent challenges and discuss alternative approaches for biochemical and cellular lysine methylation studies.

The histone variant mutation H3.3-G34W occurs in the majority of giant cell tumor of bone (GCTB). By profiling patient-derived GCTB tumor cells, the authors show that this mutation associates with epigenetic alterations in heterochromatic and bivalent regions that contribute to an impaired osteogenic differentiation and the osteolytic phenotype of GCTB.

Biochemical and modelling data explain how PRDM9 specifically methylates the very different H3K4 and H3K36 substrates by distinct substrate interaction modes. Our data illustrate evolutionary pathways for specificity swapping of PKMTs.

Cycles of DNA methylation and demethylation are observed at the pS2 gene promoter during its activation by oestrogen, accompanied by cycling of DNA methyltransferases and other factors; this contrasts with the accepted view of DNA methylation as a stable epigenetic mark.

Eukaryotic elongation factor 1 alpha (eEF1A) is subject to extensive post-translational methylation but not all responsible enzymes are known. Here, the authors identify METTL13 as an eEF1A methyltransferase with dual specificity, which is involved in the codon-specific modulation of mRNA translation.

The SET-domain containing protein 2 (SETD2) is a protein lysine methyltransferase that has been shown to methylate the super-substrate peptide ssK36 100 times faster than the corresponding natural H3K36 peptide. Here, a combination of molecular dynamics simulations and biochemical experiments are applied to identify the mechanisms responsible for the increased activity of SETD2 towards ssK36.

The authors report that DNA methylation coevolves with the DNA alkylation repair enzyme ALKB2 across eukaryotes. They also show that DNA methyltransferases cause alkylation damage in vitro and in vivo by introducing 3-methylcytosine into DNA.

Based on a specificity analysis, ATRX and FANCM are discovered as substrates of NSD2. Moreover, an artificial NSD2 super-substrate is designed that is methylated very fast due to distinct hyperactive conformations of the NSD2-peptide complex.

A biochemical study discovers that the target site preferences of the DNA methyltransferase DNMT3C differ from its relatives DNMT3A and DNMT3B and they specifically match the biological repeat elements methylated by DNMT3C.

Global introduction of m6dA into human DNA in HEK293 cells reduces their viability and directly alters their gene expression.

DNA methyltransferase 3A (DNMT3A) is shown to efficiently methylate recombinant mononucleosome linker DNA and a role for H3K36me3 in the stimulation of DNA methylation is revealed that is independent of its interaction with the PWWP domain.

Sabrina Adam et al. use a deep enzymology method to study the effect of neighboring DNA sequence variation on the in vitro activity of Tet1 and Tet2. Their results suggest that flanking sequences could represent an important parameter that influences genomic DNA modification patterns.

Schuhmacher, Beldar et al. design a super-substrate peptide based on the substrate sequence specificity of the SETD2 protein lysine methyltransferase. SETD2 methylates this super-substrate 290-fold more efficiently than the original H3K36 peptide. This study illustrates that substrate sequence design can improve the activity of protein lysine methyltransferases.

Notch and VEGF signalling controls the specification of endothelial cells to tip and stalk cells during angiogenesis sprouting. Alitalo and colleagues show that macrophage-derived VEGF-C activates VEGFR2 to contribute to the conversion of endothelial cells from a tip- to a stalk-cell fate when two sprouts fuse to ensure vessel growth and branching.

By using a CRISPR/dCas9 biosensor that reads DNA methylation of α-satellite repeats in live cells, we identify a signaling pathway linking the chromatin and transcriptional state of repeats to the integrity of epithelial adherens junctions.