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NatD is an acetyltransferase responsible for N-α-terminal acetylation of the histone H4 and H2A and has been linked to cell growth. Here the authors show that NatD-mediated acetylation of histone H4 serine 1 competes with the phosphorylation by CK2α at the same residue thus leading to the upregulation of Slug and tumor progression.

Over the past few decades, epigenetics has evolved from a collection of curious biological phenomena to a functionally dissected research field. In this article, the authors provide a personal perspective on the advances of research into epigenetics — from its historical origins to its modern era — with a focus on molecular breakthroughs.

Transposable elements in mammalian genomes need to be silenced to avoid detrimental genome instability; here, the histone variant H3.3 is shown to have an important role in silencing endogenous retroviral elements.

Phosphorylation of residues in the N-terminal tail of histone H3 signals different biological outcomes. High-resolution NMR analyses now reveal a mechanistic hierarchy of H3 phosphorylation events, whereby phosphorylation of Ser10 impedes the phosphorylation of Thr6 and Thr11 by PKC and Chk1, respectively. Because both enzymes also target Ser10, this establishes an autoinhibitory feedback loop on H3 tails.

Gates et al. show that histone butyrylation and propionylation in the intestinal epithelium are regulated by the gut microbiota and histone butyrylation is associated with gene regulatory programmes.

Missense mutations in histones can drive oncogenesis and disrupt chromatin, but the associated mechanisms for many such mutations remain poorly understood. Here, the authors show that cancer-associated histone mutations at arginines in the H3 N-terminal tail disrupt repressive chromatin domains, alter gene expression, and in one case impair differentiation via reduction of PRC2 function.

Combined use of a DNA-barcoded nucleosome library and a humanized yeast library allows the identification of histone globular domain mutations that affect histone exchange and nucleosome sliding processes, as well as cancer-associated gene pathways.

Previous studies have reported MLL-AF4 binding at intragenic and intergenic enhancers, however, the role of MLL-AF4 in enhancer function remains to be investigated. Here, the authors show that MLL-AF4 cooperates with PAF1 and FACT at enhancers to promote high-density interactions with oncogene promoters in leukemia.

Increasing evidence suggests crucial functions for histone variants in diverse biological processes. This Review examines the roles of histone variants in mammalian germ cell and embryonic development, as well as the consequences of their aberrant regulation in human disease.

ATR-X syndrome is a congenital disease linked to mutations in ATRX. The ADD domain in ATRX is now found to form a new histone H3 recognition module with binding being promoted by H3K9me3 and antagonized by H4K4me3. Co-crystal structures indicated that H3K9me3 is bound in a polar pocket formed between a GATA-like and PHD domain. Loss of this binding leads to ATRX mislocalization in vivo and has been linked to ATR-X syndrome.

Proteins that interact with histone post-translational modifications have now been identified using an approach based on split-intein mediated histone semisynthesis. Histone modifications and disease-relevant mutations were installed into native chromatin with an adjacent photocross-linker to enable in situ cross-linking. This strategy enabled the determination of chromatin-relevant interactomes and represents a powerful tool for exploring epigenetic regulation and dysregulation at the molecular level.

A high-throughput approach using a DNA-barcoded nucleosome library shows that ISWI chromatin remodellers can distinguish between differently modified nucleosomes.

Memory formation requires gene transcription, but the link between synaptic activity and transcription is not fully understood. Brd4 regulates transcription in other cell types and Brd4 family inhibitors are in clinical trials for cancer. The authors show that Brd4 is important for activity-dependent gene transcription in neurons and memory consolidation.

The histone-acetylation-reader protein ENL is mutated in a paediatric kidney cancer in such a way that it clusters at target genes, increasing the recruitment of the transcriptional machinery, enhancing transcription and deregulating cell fate during development.

Increasing evidence indicates that misregulation of histone modifications can contribute to cancer. This Review summarizes how misreading, miswriting and mis-erasing histone methylation marks are involved in tumorigenesis and progression, by deregulating gene expression and perturbing cellular identity.

In pancreatic neuroendocrine tumors (PanNETs) ATRX, DAXX, and MEN1 are commonly mutated (A-D-M mutant PanNETs). Here, the authors find in a cohort of PanNETS 58% are A-D-M mutant PanNETs, with a worse clinical outcome and differences in gene expression and methylation compared to A-D-M wild type cases- these gene expression differences suggest that A-D-M mutant PanNETs potentially originate from a cell type similar to alpha cells.

Mutations in histone H1 induce the remodelling of chromatin architecture to a more relaxed state, which leads to malignant transformation through changes in histone modifications and the expression of stem cell genes.

DNMT3A PWWP domain mutations promote localization of DNMT3A to CpG islands in a PRC1-dependent manner. DNMT3A interacts with H2AK119ub-modified nucleosomes.

Finley et al. show that Brd4 is dispensable for self-renewal and pluripotency in murine embryonic stem cells (ESCs). In metastable ESCs, Brd4 independence can be achieved by increasing the expression of the pluripotency transcription factors Oct4, Sox2 and Nanog as long as Tet1/2 are present.

An inhibitor of the YEATS domain was developed by targeting a unique π-π-π stacking in the YEATS–Kcr recognition. An ENL YEATS-selective inhibitor, XL-13m, helps probe the YEATS-dependent role of ENL in the leukemogenic transcription program.

An epistatic miniarray profile allows identification of multiprotein complexes involved in various aspects of chromosome biology. In one pathway, the histone acetyltransferase Rtt109 is found to modify histone H3 lysine 56 during DNA replication.

Ribosomal DNA transcription is essential for cell growth and division. Here, the authors show that EMT is accompanied by Snail binding to rDNA operons and Rictor association with nucleoli to fuel an induction of ribosome biogenesis during G1/S cell cycle arrest and inhibition of ribosome biogenesis hampers EMT, differentiates primary tumors and reduces metastasis.

An early cellular response to the occurrence of DNA double-strand breaks in mammals is the phosphorylation of the specialized histone variant H2A.X at Ser 139. The chromatin remodelling factor WSTF is found to phosphorylate H2A.X at another site, Tyr 142. Tyrosine phosphorylation has not been observed previously on histones.

One of four papers establishing certain PHD domains as effectors of trimethylated histone H3K4, a chromatin mark generally associated with active transcription. This paper shows that the interaction of H3K4me3 with the PHD finger of an ATP-dependent chromatin remodelling complex is involved in control of Hox gene expression during Xenopus development.

H3K36me2 targets DNMT3A to intergenic regions and this process, together with H3K36me3-mediated recruitment of DNMT3B, has a key role in establishing and maintaining genomic DNA methylation landscapes.

Mammalian gene silencing is associated with both histone and DNA methylation. The PRMT5 arginine histone methyltransferase is now found to affect DNA methylation at the γ-globin locus in mice. This is mediated by an effect on recruitment of the DNA methyltransferase DNMT3A, but through interaction with the product of PRMT5 activity. This suggests that DNMT3A reads the histone methylation, coupling it to nearby DNA methylation.

Comprehensive sequencing of benign and malignant tumors has recently uncovered new driver mutations in childhood tumors. A new report now describes frequent histone H3.3 alterations in chondroblastoma and giant cell tumor of bone, emphasizing the importance of this histone variant in pediatric cancers.

One of four papers establishing certain PHD domains as effectors of trimethylated histone H3K4, a chromatin mark generally associated with active transcription. This paper provides structural insight into the recognition of H3K4me3 by the PHD finger of BPTF, a subunit of the chromatin-remodelling complex NURF.

DNMT3L, a regulatory factor related in sequence to DNA methyltransferases, is shown to interact with the N terminus of histone H3 and this interaction is inhibited by methylation at lysine 4. This suggests DNMT3L could respond to states of histone modification to regulate de novo DNA methylation.