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The actin methyltransferase SETD3, by virtue of its ability to interact with the viral 2A protein and independently of its enzymatic activity, is necessary for RNA replication of several enteroviruses in cell culture and in vivo.

Binding of the transcription factor NF-κB subunit RelA activates proinflammatory gene expression. Gozani and colleagues show that basal expression of RelA target genes is suppressed by methylation of RelA by SETD6, which triggers repressive histone methylation by GLP.

The lysine methyltransferase SMYD5 and its newly identified substrate ribosomal protein L40 are implicated in the progression of gastric adenocarcinoma, and ablation of SMYD5 prevents metastatic disease in mouse models of this cancer.

The histone H3K36 methyltransferase NSD3, which is associated with the common 8p11–12 chromosomal amplification, is an oncogenic driver in lung squamous cell carcinoma.

Numerous methylated residues exist on histone tails, the functional significance of which remains unknown. New studies in budding yeast now identify monomethylation of histone H4 lysine residues 5, 8 and 12 as functionally important marks that regulate cell growth and stress responses and are catalyzed by the first known H4 methyltransferase in budding yeast, Set5.

Actin histidine methyltransferase SETD3 is a host factor critical for the replication of enteroviruses. Here, the authors report the 3.5 Å cryoEM structure of SETD3 interacting with enterovirus CV-B3 2A protease, defining the actin-binding SET ___domain as essential for virus replication.

Protein lysine methylation is an important post-translational modification of histone and non-histone proteins. In this Review, Gozani and colleagues discuss the role of protein lysine methyltransferases, the ‘writers’ of protein lysine methylation, in a range of diseases, and the progress and potential of targeting these enzymes therapeutically. They also consider the biology of lysine methyltransferases beyond epigenetic regulation as emerging targets for drug discovery.

SETD3 methylates mammalian actin at His73, and SETD3 deficiency impairs stimulus-induced contraction in primary human uterine smooth muscle cells and leads to maternal dystocia in mice.

Husmann and Gozani review the biochemical and biological activities of histone lysine methyltransferases and their connections to human diseases, focusing on cancer.

SMYD3 is a methyltransferase overexpressed in several human tumours; here methylation of the MAP3K2 kinase by SMYD3 is shown to be critical for Ras-induced tumour development in mouse models and human tumour cells, showing an unexpected role for methylation in a kinase signalling pathway and revealing a candidate therapeutic target.

Cryo-electron microscopy structures of the nucleosome-bound NSD2 and NSD3 histone methyltransferases reveal the molecular basis of their histone modification activity, and show how mutations in these proteins can lead to oncogenesis.

The Sir2 family member SIRT6 is an NAD-dependent, histone H3 lysine 9 deacetylase enzyme that modulates telomeric chromatin and is required for stable association of WRN, the factor that is mutated in Werner Syndrome.

BHC80 is a component of the LSD1 co-repressor complex that demethylates histone H3 at lysine 4. The PHD ___domain of BHC80 interacts with the histone H3 tail only when lysine 4 is unmethylated, and BHC80 function is coupled to that of LSD1 in gene repression.

One of four papers establishing certain PHD domains as effectors of trimethylated histone H3K4, a chromatin mark generally associated with active transcription.

The interaction between H3K4me3 and the ING2 PHD ___domain is enhanced after DNA damage, recruiting the repressive complex to the promoters of proliferation genes.

SETD3 is the first known metazoan protein histidine methyltransferase but the molecular basis for its target specificity is unclear. Here, the authors elucidate the structural and molecular determinants for the histidine specificity of SETD3.

One of four papers establishing certain PHD domains as effectors of trimethylated histone H3K4, a chromatin mark generally associated with active transcription. This paper describes the structure of the PHD finger from the tumour suppressor ING2 complexed with H3K4me3.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here Kuo and colleagues uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

How histone modifications crosstalk with DNA methylation to regulate epigenomic patterning and genome stability in mammals remains elusive. Here, the authors show that DNA methyltransferase DNMT1 is a reader for histone H4K20 trimethylation via its BAH1 ___domain, which leads to optimal maintenance of DNA methylation at repetitive LINE-1 elements.

The identification of the regulatory protein ENL as essential to an aggressive form of leukaemia provides insight into transcriptional regulation and highlights potential avenues for therapy. See Letters p.265 & p.270

A crystal structure of the tandem PHD and bromodomain regions of the transcription and chromatin regulator TRIM24 reveals combinatorial recognition of dual marks on the histone H3 tail. TRIM24 is involved in activation of oestrogen-dependent genes and is aberrantly expressed in breast cancer.

The ATLAS Collaboration reports the observation of the electroweak production of two jets and a Z-boson pair. This process is related to vector-boson scattering and allows the nature of electroweak symmetry breaking to be probed.

SIRT7 is an H3K18Ac-selective deacetylase that has a pivotal role in chromatin regulation, maintenance of cellular transformation programs and tumour formation in vivo.

RAG2, a component of the V(D)J recombinase, has a plant homeodomain (PHD) ___domain which specifically recognizes histone H3 trimethylated at lysine 4 (H3K4me3). A crystal structure of the complex is presented, and the interaction between RAG2 and H3K4me3 shown to be important for V(D)J recombination in vivo.

Methylation of H3K27 by Polycomb repressive complex 2 (PRC2) is essential for gene regulation. A new study provides structural evidence for the recognition of di- and trimethylated H3K36 by the Tudor ___domain of PRC2 subunit Phf19 as well as functional data suggesting that recognition of di- or trimethylated Phf19–H3K36 is required for regulating PRC2 activity and for full repression of selected PRC2 targets in embryonic stem cells.

The development of an epigenetics-focused, CRISPR-based high-content functional genomics screening platform provides insight into chromatin regulation and uncovers a potential strategy to treat an aggressive type of leukemia.

It is shown here that the methylation of histone proteins regulates lifespan in Caenorhabditis elegans. Deficiencies in members of the ASH-2 complex, which trimethylates histone H3 at lysine 4 (H3K4), extend worm lifespan. Meanwhile, the H3K4 demethylase RBR-2 is required for normal lifespan. These findings are consistent with the idea that an excess of H3K4 trimethylation reduces longevity. The extension of lifespan caused by ASH-2 deficiency requires an intact adult germline and the continuous production of mature eggs.

Using the semiconductor synthesis technology of maskless photolithography on microprocessor-grade silicon wafers, Jordan Price and colleagues synthesized microarrays containing every possible overlapping peptide in a linear sequence covering the N terminus of human histone H2B, including post-translational modifications. They demonstrated use of the 'on silico' peptide microarrays for the high-resolution mapping (at the single amino acid level) of epitopes targeted by commercially available H2B-specific antibodies and also by autoantibodies in samples from individuals with systemic lupus erythematosus.

The ORC1 BAH ___domain is shown to be a module that recognizes a histone modification associated with replication origins, providing insight into the aetiology of Meier–Gorlin syndrome.