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Silencing of endogenous retroviral elements (ERVs) is mediated by KAP1. Here, the authors describe the molecular mechanism by which KAP1 induces structural reorganization and multimerization of HP1α and maintains inaccessible chromatin at ERVs in mouse embryonic stem cells.

Chemicals derived from neurotransmitter molecules in the brain can act as epigenetic marks on histone proteins to regulate gene expression. These marks control circadian clock genes and influence behaviour.

Mutations of the histone H3K36-specific methyltransferase ASH1L have been linked to several human diseases. Here, the authors report the mechanism by which three C-terminal domains in ASH1L regulate its enzymatic activity and interact with chromatin.

Epigenetic coregulators ENL (eleven-nineteen-leukemia) and MOZ (monocytic leukemia zinc finger) are implicated in leukemias. Here, the authors report the acetylation-dependent and acetylation-independent mechanism for the ENL–MOZ complex formation and show the colocalization of ENL and MOZ at active promoters.

YEATS domains are histone acylation readers that recognize crotonyllysine and acetyllysine. Here the authors provide structural insights into how YEATS domains recognize acetyllysines and further show that the human AF9 YEATS domain also binds DNA.

JADE is a subunit of human acetyltransferase complex HBO1 that is essential in transcriptional regulation. Gaurav et al. characterize the molecular mechanism by which JADE mediates genomic association and enzymatic and pathological activities of the HBO1 complex.

The chromatin remodeller CHD4 contains two PHD finger reader domains that have been shown to bivalently recognize H3 histone tails. Here, the authors describe a mechanism by which the PHD fingers bind to the intact nucleosome core particle, revealing both cooperative and individual interactions.

Human methyltransferase MLL4 mediates embryonic development and is dysregulated in diseases. Zhang et al. found that binding of PHD fingers of MLL4 to ASXL1/2 is required for recruitment of the deubiquitinase BAP1 to MLL4-bound active enhancers in vitro.

The yeast NuA3 complex regulates gene transcription and the cell cycle. Nguyen et al. show that intersubunit interactions involving the Taf14, Yng1 and Sas3 subunits are essential in biological activities of the NuA3 complex.

Inhibitor of apoptosis BIRC2 mediates cell death and survival. Tencer et al. report the molecular mechanism underlying BIRC2 cellular localization and describe the effect of BIRC2 inhibition on the death of cancer cells and HIV-1-infected T cells.

Inositol tetraphosphate is required for both the incorporation of the histone deacetylase HDAC3 into a repressive complex and its enzymatic activity.

Here the authors report that the Taf2 and Taf14 subunits of the yeast TFIID complex interact and mediate binding to chromatin. Binding of Taf2 to Taf14 promotes a conformational rearrangement in Taf14, resulting in a release of the linker region for the engagement with the nucleosome and their association with DNA is essential for transcriptional regulation.

Human Microrchidia 4 (MORC4) ATPase has been implicated in acute and chronic pancreatitis, inflammatory disorders and cancer. Here the authors describe the structure–function relationship of MORC4 and define the molecular mechanism for MORC4 activation.

Structural and biochemical analyses identify the ZZ domain of p300 as a novel histone H3–binding module that promotes p300 chromatin association and is required for selective acetylation of H3K18 and H3K27 in human cells.

Histone methyltransferase MLL4 is a transcriptional regulator. Here the authors identify the PHD6 finger of MLL4 as a selective reader of the epigenetic modification H4K16ac and show that a subset of MLL4 chromatin binding sites overlap with H4K16ac-enriched regions, which depends on MOF activity.

Human acetyltransferases MOZ and MORF mediate development programs and are dysregulated in diseases. Here the authors identified two winged helix (WH) domains in MORF/MOZ and characterized their DNA binding functions, including targeting of CpG by WH1.

Acetylation of histone H3K23 has emerged as an essential posttranslational modification, yet this epigenetic mark remains poorly understood. Here, the authors identify the native MORF complex as a histone H3K23-specific acetyltransferase and show that interaction of the MORF subunit with acylated H3K14 promotes acetylation of H3K23 by this complex to activate transcription.

Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of AML. Here, the authors report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and provide evidence of a direct link between the association of NUP98-PHD finger chimeras with H3K4me3-rich regions and leukemic transformation.

The histone acetyltransferase p300 mostly localizes to active chromatin; however, some repressed genes marked with H3K27me3 are also bound by p300. Here the authors show p300 is capable of phase separation, which relies on its catalytic core, and that p300 catalytic activity is decreased in phase-separated droplets that co-localize with H3K27me3-marked chromatin.

Binding of the Tudor domain of the PHD finger protein PHF1 to H3K36me3 inhibits Polycomb PRC2 complex methyltransferase activity. Here, Musselman et al.characterize this interaction in the context of the full nucleosome and show dual binding of the PHF1 Tudor domain to H3K36me3 and double-stranded DNA.

Chromosomal translocations involving the AF10 gene, especially with CALM, are associated with aggressive leukemias. Here the authors show that the PZP domain of AF10, a histone reader, is always excluded/impaired in AF10 fusions, whereas incorporation of this domain downregulates Hoxa genes and blocks leukemogenesis.

Histones are recognized by epigenetic readers, which play essential roles in regulation of chromatin and transcription. Here the authors provide evidence that the ZZ-type zinc finger domain of ZZZ3 functions as a reader of histone H3, which is required for the ATAC complex-mediated maintenance of histone acetylation and gene activation.

Engineered demethylase LSD1 opens a new avenue in developing tools to study intricate relationships between histone post-translational modifications that can be enzymatically edited.

Over the past decade, remarkable breakthroughs in our understanding of epigenetic biology have coincided with an increased public interest in the impact of diet and lifestyle choices on health. It is well established that a balanced diet enhances life expectancy and helps to prevent or treat certain diseases, such as obesity, diabetes, cancer, and mental disorders. However, the biological mechanisms underlying these effects are not yet well understood. In this commentary, we highlight several recent studies that report on a potential link between dietary factors and alterations in epigenetic pathways, providing compelling insight into the possible effects of environmental factors on fundamental biological processes.

The human Polycomb-like protein PHF1 has been implicated in transcription-regulatory and DNA damage repair pathways. A new study demonstrates that the Tudor domain of PHF1 binds histone H3K36me3 with high specificity and affinity, that Tudor-H3K36me3 interaction inhibits Polycomb repressive complex 2-mediated H3K27 methylation and that PHF1 accumulates at DNA damage sites in a Tudor-dependent manner.

The autophagic receptor p62 recognizes arginylated (Nt-R) substrates through its ZZ domain (p62_ZZ). Here the authors identify a p62 auto regulatory mechanism and provide structural insights into the selective recognition of Nt-R by p62_ZZ and further show that Nt-R binding stimulates p62 oligomerization and macroautophagy.

Amid the COVID-19 pandemic, scientists around the globe have been working resolutely to find therapies to treat patients and avert the spreading of the SARS-CoV-2 virus. In this commentary, we highlight some of the latest studies that provide atomic-resolution structural details imperative for the development of vaccines and antiviral therapeutics.

Identifying chromatin modifications and their interactomes is imperative to understand how chromatin functions and is regulated. Now, two new studies report on chemical tools that enable characterization of the biological interactions within native chromatin.

In a stress-free environment, the histone binding function of 53BP1 is inhibited by TIRR, but upon DNA damage 53BP1 is recruited to chromatin and promotes DNA repair. New structural studies provide insights into the mechanisms underlying 53BP1 inhibition and activation. TIRR physically blocks the methyl-lysine histone-binding site of Tudors, and RNA binding by TIRR alleviates this block.

Chromatin is compartmentalized spatially and temporally at multiple levels, but the precise organization of chromatin and mechanisms underlying its restructuring remain unclear. Two studies published in Cell and Nature now demonstrate the ability of chromatin to undergo liquid–liquid phase separation under physiological conditions and show that this intrinsic physicochemical property of chromatin can be regulated.

Crotonylated lysine residues within histones are linked to transcriptional activation in a process involving histone mark ‘reader’ proteins. Crystallographic analysis of the YEATS domain of the Taf14 protein reveals a mode of crotonylated histone mark recognition via a π-sandwich motif.

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.

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.

A number of histone lysine modifications related to acetylation have been identified, but their functional significance is unclear. Here, the authors use in vitro and in vivo assays to characterize eight acyl histone post-translational modifications and link their abundance with metabolism.

E2F1, which localises to DNA double-strand breaks (DSBs) to promote repair, is acetylated in response to DNA damage but the role this plays in DNA repair is unknown. Here the authors show that E2F1 acetylation creates a binding motif for the bromodomains of the p300/KAT3B and CBP/KAT3A acetyltransferases, which is required for recruitment of p300 and CBP to DSBs, to facilate repair.

The histone methyltransferase G9a methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. Here, Zhang et al. show that methylation of ERα by G9a recruits the PHF20/MOF complex that deposits histone H4K16 acetylation promoting active transcription.

Profiling of a combinatorial library of post-translationally modified histone H3–based peptides reveals that Thr3 phosphorylation, Arg2 methylation and Thr6 phosphorylation can modulate recognition of Lys4 methylation status by PHD fingers. Additionally, Thr6 phosphorylation, a previously undescribed modification, is shown to exist in native histones.

Histone modification recognition is an important mechanism for gene expression regulation in cancer. Here, the authors identify YEATS2 as a histone H3K27ac reader, regulating a transcriptional program essential for tumorigenesis in human non-small cell lung cancer.

A Perspective focused on post-translational modifications of histone proteins and their selective recognition by epigenetic 'readers' highlights the importance of structural insights in understanding these key interactions in gene expression regulation.

Histone post-translational modifications (PTMs) can directly influence histone-DNA and histone-histone interactions, or they can be targeted by protein effectors, or histone readers. This Review outlines known readers of histone PTMs, details their mechanism of action and the functional significance of histone PTM recognition and discusses cross-talk between protein effectors and consequences of the combinatorial readout of PTMs.

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.