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Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Monomethylation of histone H4 lysine 20 (H4K20me1) contributes to DNA replication but the mechanism is not well understood. Here, the authors identify a conserved tandem Tudor domain of BAHCC1 as a H4K20me1-specific reader, which promotes the recruitment of MCM complex to chromatin for efficient DNA replication.

Starble, Sun, and colleagues identify an epigenetic priming mechanism that promotes oncogene amplification in acquired resistance to tyrosine kinase inhibitors and establishes a role of METTL7A in this process.

Trinucleotide-repeat-containing 18 (TNRC18), which has poorly understood functions, is now identified as an H3K9me3-specific reader that silences endogenous retroviruses.

DNMT3A-nucleosome interaction underpins the genomic DNA methylation landscape. Here, the authors investigate how an N-terminal fragment of DNMT3A recognizes the H2AK119ub1-marked nucleosome, providing insights into the chromatin-targeting mechanism of DNMT3A.

A BAH module in BAHCC1 recognizes H3K27me3 and is involved in gene silencing. BAHCC1 is highly expressed in acute leukemia cells and contributes to their proliferation.

Wang et al. reveal a noncanonical mechanism for EZH2 in binding the oncoprotein cMyc to promote tumorigenesis, and develop a small-molecule degrader, MS177, to target both canonical and noncanonical functions of EZH2 to suppress tumour growth.

The NUP98–HOXA9 oncogenic fusion protein found in leukaemia undergoes phase separation in the nucleus, which helps to promote activation of leukaemic genes and to establish aberrant chromatin looping.

DNMT3A R882H and R882C are mutation hotspots in acute myeloid leukemia. This study describes the structural and functional consequences of the DNMT3A R882H/R882C mutations which can provide a strategy for therapy of the disease mutations.

EGLN2 hydroxylates histone H3 at proline 16, enhancing the binding of KDM5A to H3K4me3. Genome- and transcriptome-wide analyses show that the EGLN2–KDM5A axis regulates target gene expression in mammalian cells.

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.

In mammals, de novo DNA methyltransferase DNMT3B is essential for establishing DNA methylation patterns during embryonic development. Here the authors provide a structure-function characterization of homo-oligomeric DNMT3B, revealing the molecular basis for its vulnerability to ICF mutations.

Intensity-rotating beams are a class of structured beams that can potentially enable advanced optical manipulation techniques, as well as applications in free-space optical communication and high-resolution imaging, but their exploration has remained mostly theoretical. The authors demonstrate galactic-form spinning beams, i.e a stable, intensity-rotating beam whose dynamics and divergence can be precisely controlled.

A crystal structure of DNMT3A and its regulatory partner DNMT3L bound to DNA reveals the mechanistic basis for DNMT3A-mediated DNA methylation and establishes its aetiological link to human disease.

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 fusion gene ZMYND11-MBTD1 (ZM) is present in a subgroup of patients with acute myeloid leukaemia (AML). Here, the authors show that ZM expression induces AML in a murine model though activating the NuA4/TIP60 histone acetyltransferase complex.

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

The N6-methyladenosine (m⁶A) RNA modification is an evolutionarily conserved epitranscriptomic mechanism that impacts several cellular processes. Here the authors present a structure-function analysis of the ZCCHC4, 28S RNA-specific m⁶A methyltransferase, shedding light on its regulation and mechanisms that ensure substrate specificity.

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 Argonaute (Ago) family of proteins provides the slicer activity of the RNA-induced silencing complex, with the Ago component of the complex providing the catalytic residues governing guide-strand mediated site-specific cleavage of target RNA. Here, the crystal structures of ternary complexes of Thermus thermophilus Ago catalytic mutants are reported and analysed.

Additive manufacturing methods at the macroscale have seen significant advances in recent times, but advances for the bottom-up formation of nanoscale polymeric features are yet to be realized. Here, the authors demonstrate that rapid crosslinking of an AFM delivered norbornene crosslinker in presence of a surface-tethered metathesis catalysts facilitates the curing of delivered material in an extremely rapid fashion

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.

Deregulation of chromatin modification underlies a myriad of oncogenic processes. This Review synthesizes the many connections between chromatin modifications and cancer, discussing recent advances and highlighting options for therapeutic targeting.