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The uterus undergoes successive rounds of pregnancy associated tissue remodelling. Here they show that Blimp1/PRDM1 activity is required in the uterine stroma during both gestational and post-partum uterine repair in the mouse.

PBK is a mitotic kinase implicated in cancer. This study reveals how PBK evicts key C2H2-zinc finger transcription factors such as Ikaros, Aiolos and CTCF from DNA as cells divide, regulating mitotic chromatin accessibility and chromosome compaction.

Promoter escape is a key step in bacterial transcription and a target of the antibiotic rifampicin. Here, the authors use cryo-EM to explore this step, finding seven structural intermediates of M. tuberculosis RNA polymerase during promoter escape.

Zinc finger nucleases have an established role in genome editing. Here, the authors report a strategy for identifying zinc finger nucleases that discriminate between desired targets and provide genome-wide specificity.

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.

Context-dependent assembly (CoDA) of zinc finger nucleases is reported. Starting from an archive of zinc finger modules known to function well together, effective multifinger arrays can be constructed using standard techniques. Also in this issue, Doyon et al. report rational design of nucleases with improved cleavage activity.

Hockemeyer et al. demonstrate targeted genetic modification of three genes in human embryonic stem cells and induced pluripotent stem cells using zinc-finger nucleases delivered on plasmids. They use the approach to generate a reporter cell line that monitors the pluripotent state, a drug-inducible overexpression system, and a reporter cell line for a gene that is not expressed in pluripotent stem cells.

Transcription factor osr2 is identified as a specific marker and regulator of mural lymphatic endothelial cell (muLEC) differentiation and maintenance, and muLECs and border-associated macrophages share functional analogies but are not homologous, providing an example of convergent evolution.

Liu and colleagues demonstrate that biomimetic fractal patterns derived from glomerular histology can enhance the maturation of podocytes (highly differentiated glomerular cells) that are grown in culture. This work presents a bioengineered platform for improved cell culture fidelity.

Lu et al. reveal the spatiotemporal coordination between two nucleation-promoting factors, WAVE and N-WASP, and two actin-bundling proteins, dynamin and WIP, in generating invasive protrusions at the mammalian myoblast fusogenic synapse.

Haque et al. report that the Hedgehog pathway kinesin KIF7 binds the transcription factor GLI via electrostatic coiled-coil interactions, and synergy between KIF7 and GLI underlies the recruitment of both proteins to microtubules and the cilium tip.

Radical Fe^II/α-ketoglutarate-dependent halogenases are powerful biocatalysts for C–H functionalization. Here, the authors reveal the mechanistic basis for chemoselectivity in a lysine halogenase.

Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

Epigenetic editing has emerged as a powerful hit-and-run approach to precise modification of gene expression without altering the underlying DNA sequence. This Review explores the therapeutic potential of epigenetic editing, highlights tools and concepts, assesses challenges and considerations, discusses in vivo studies and examines approaches and agents entering clinical development.

The bacterial ubiquitin ligase NleL evades host defence mechanisms both by inhibiting pyroptosis and by preventing infected intestinal epithelial cells from being extruded into the lumen and expelled in the faeces.

MORC2, a chromatin remodeler involved in epigenetic silencing and DNA repair, is linked to cancer and neurological disorders when dysregulated. Here, the authors show that MORC2 binds DNA at multiple sites, clamps onto it, and induces compaction, a process regulated by its phosphorylation.

To date, experimental induction of hair cell regeneration in mammals leads to immature and poorly differentiated hair cells. Here the authors show that the transcription factor prdm1a plays a crucial role in specifying sensory hair cell types with loss of prdm1a in zebrafish leading to misspecification of hair cells in the sensory lateral line system into ear hair cells.

Serological detection of antibodies against SARS-CoV-2 can help establish rates of seroconversion. Here the authors develop a red cell agglutination test to detect antibodies against the receptor binding domain for distribution free of charge to qualified research groups.

Induced proximity modalities encompass monovalent and bifunctional agents, such as molecular glues and proteolysis-targeting chimeras, that induce an interaction between biomolecules to functionally modulate the target. This Review highlights seminal discoveries in the field, surveys the various modalities and discusses novel approaches to control cellular processes beyond protein degradation.

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Initiation of HIV-1 reverse transcription occurs at the host tRNA^Lys₃, which forms a complex with the 5’ end of the HIV-1 viral RNA and reverse transcriptase (RT). Here, the authors present the 2.8 Å cryo-EM structure of a minimal HIV-1 RT–vRNA–tRNA^Lys₃ initiation complex (miniRTIC), and miniRTIC structures with the bound non-nucleoside reverse transcriptase inhibitors nevirapine and efavirenz at 3.1 and 2.9 Å resolution, respectively.

Pirh2 is one of several ubiquitin ligases known to modify and negatively regulate p53. Solution studies reveal the structures of the three Pirh2 domains and indicate that the C-terminal domain of Pirh2 interacts with the p53 tetramerization domain. Additional data suggest that Pirh2 preferentially modifies the tetrameric, transcriptionally active form of p53 for proteasome-mediated degradation.

After RNA release, Escherichia coli RNA polymerase (RNAP) stays on DNA in a post-termination complex (PTC). PTCs can initiate RNA synthesis but produce cytotoxic R-loops. RapA induces an RNAP conformational change, dissociating PTCs and controlling R-loop formation.

The pioneer transcription factor Zelda is essential for the reprogramming of germ cells to totipotent cells of the early Drosophila embryo. Here the authors examine the function of Zelda later in development in the larval brain to show that Zelda promotes the undifferentiated stem-cell fate. They further identify factors that limit the reprogramming capacity of this pioneer factor.

Khan et al. show that Sec18 uses both D1 and D2 AAA+ rings cooperatively, opening them laterally for SNARE substrate loading and for subsequent release of SNAREs.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Resistance to rifamycin antibiotics, which target bacterial RNA polymerases, is a growing problem. Here, the authors identify gene clusters from soil metagenomes encoding production of rifamycin analogues that are active against rifampicin-resistant bacteria through a distinct mechanism.

CBFA2T3-GLIS2 is a fusion oncogene found in a subset of pediatric acute megakaryoblastic leukemia associated with a poor prognosis. Here, Garfinkle et al. map the gene regulatory network of CBFA2T3-GLIS2 using a humanized murine model and identify signaling pathways required for leukemogenesis.

The zinc finger transcriptional repressor Prdm1/Blimp1 is essential for remodelling maternal blood vessels in a subset of trophoblast cells. Here, the authors perform single-cell RNA-seq analysis on this Blimp1+ lineage, identifying functionally distinct cell types present at the maternal–foetal interface.

An optofluidic device rapidly detects, via surface-enhanced Raman scattering, picomolar concentrations of biomarkers for traumatic brain injury in finger-prick blood samples from patients.

How Nodal and Bmp pathways interact during primordial germ cell (PGC) formation remains unclear. Here, the authors show Nodal signalling via Eomes in the epiblast, together with Smad2 in the visceral endoderm, regulates formation of the mouse PGC lineage, while Smad1 specifies PGCs and Smad4 controls PGC migration.

PUF proteins, conserved stem cell regulators, maintain germline stem cells with partner proteins in nematodes. Here, authors discover a complex of two FBF-2 PUF proteins and partner LST-1 that represses target mRNA via adjacent regulatory elements.

The antibody response to COVID-19 vaccines varies among individuals. Here the authors find that older age, male sex, smoking, higher BMI, vaccine type, and certain comorbidities are associated with lower anti-S1 antibody levels after COVID-19 vaccinations, indicating that certain groups might benefit from higher frequency or doses of vaccination.

Hamish Scott and colleagues report that germline mutations in GATA2 segregate with myelodysplastic syndrome and acute myeloid leukemia in four pedigrees. The resulting alterations occur in a conserved zinc finger DNA-binding domain of GATA2.

The transcriptional repressor Blimp1/PRDM1 regulates cell fate decisions in the developing embryo and adult tissues. Here the authors show that conditional inactivation within maternal uterine tissues results in a defective primary decidual zone barrier, increased expression of inflammatory cytokines IFN gamma and Csf1, and early embryonic lethality during pregnancy.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

A multidimensional feature-based approach reveals subtle, task-dependent interactions between brain regions and networks, providing a sensitive method to study the neural basis of flexible behaviour.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

A novel antiviral targeting the SARS-CoV-2 PLpro protease shows strong efficacy in a mouse model, preventing lung pathology and reducing brain dysfunction. The study provides proof-of-principle that PLpro inhibition may be a viable strategy for preventing and treating long COVID.