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A new DNA ‘base editor’ can change targeted A•T base pairs to G•C, allowing disease-associated mutations to be corrected and disease-suppressing mutations to be introduced into cells.

Analysis of rare protein-truncating, damaging missense and copy number variants from exome sequencing of 63,237 individuals identifies 72 genes associated with autism spectrum disorder.

Notch signalling plays a key role in cell fate transitions, but how Notch activates distinct regulatory networks in closely related cell types is not well understood. Here the authors profile Notch and RBPJ targets in the developing mouse cortex and reveal how transcription factor occupancy and chromatin remodelling interact to direct differential gene expression during differentiation.

Whole-exome sequencing in a large autism study identifies over 100 autosomal genes that are likely to affect risk for the disorder; these genes, which show unusual evolutionary constraint against mutations, carry de novo loss-of-function mutations in over 5% of autistic subjects and many function in synaptic, transcriptional and chromatin-remodelling pathways.

Targeted DamID (TaDa) extends DamID to enable cell-type-specific profiling of genome-wide protein binding. Transcription factor binding sites, RNA Pol II occupancy and chromatin states can be studied to provide insights into cell-fate specification.

Engineered variants of DNA base editors have reduced RNA off-target editing while retaining DNA on-target efficiency.

Integrated analyses in a large collection of families provide insights into the combined effects of rare variants and polygenic risk on autism spectrum disorder.

Thetad (tight adherence) genes of Aggregatibacter actinomycetemcomitansspecify the production of adhesive pili that function in biofilm formation, colonization and pathogenesis of this periodontal pathogen. The article reviews the evidence that the Tad secretion system represents a widespread new type of prokaryotic secretion system that has important functions in different bacterial pathogens.

CRISPR-Cas9 technology holds the potential to treat a wide spectrum of genetic diseases. Here, the authors describe a modular platform for extracellular vesicle-based Cas9 delivery, using MS2-based RNA-binding domains and UV-cleavable linkers, suitable for various Cas9-based moieties.

The Tad pilus is involved in the formation of antibiotic-resistant biofilms in many bacteria, including the human pathogen Pseudomonas aeruginosa. The authors report the structure of the Tad pilus protein RcpC, demonstrating that it forms its alignment complex, bridging the inner and outer-membrane elements.

The ATPase CpaF from C. crescentus powers pilus dynamics in the bacterial Tad pilus system. Cryo-EM and light microscopy characterisation of CpaF uncovers a mechanism for how CpaF may drive both pilus extension and retraction.

RNA-DamID, a novel approach to detect lncRNA–genome interactions in vivo with high sensitivity and accuracy, demonstrates that the initial targeting of lncRNAs in the Drosophila dosage-compensation complex is cell-type specific.

An analysis of rare genetic variants identifies three genes—MAP1A, ANO8 and ANK2—that have a role in attention deficit hyperactivity disorder (ADHD) and investigates the potential underlying biological mechanisms.

The safety and efficacy of ribonucleoproteins for genome editing can be enhanced by formulations of lipid nanoparticles optimized for enhanced stability, delivery efficiency and editing potency of the protein complexes.

Engineering a mutant-specific customized base editor precisely corrects a mutation while minimizing bystander edits, leading to substantial phenotypic recovery in mouse models of multisystemic smooth muscle dysfunction syndrome.

Intravenous delivery of an adenine base editor and a single-guide RNA for the Fah gene can correct an A>G splice-site mutation in an adult mouse model of tyrosinaemia.

A base editor that concurrently modifies both adenine and cytosine broadens the potential applications of base editing.

While prime editing is a promising technique, some genomic sites remain difficult to edit. Here the authors present fluoPEER, fluorescent prime editing and enrichment reporter, to rank the efficiency of pegRNAs and prime editor variants.

CRISPR DNA base editors induce transcriptome-wide off-target RNA editing, which can be reduced by using engineered variants that retain on-target DNA editing activities.

While progress in early human cortical development is acknowledged, a limited understanding persists regarding transcriptomic and translational profiles in subplate neurons. Here, the authors discovered an enrichment of autism spectrum disorder risk genes in subplate neurons, underscoring the crucial role played by the RNA-binding protein CELF4 in translating synaptic mRNAs during neocortical development.

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations.

Adult stem cell-derived organoids closely resemble their tissue of origin. This Review discusses recent developments in CRISPR-mediated genome engineering and its application using adult-stem-cell-derived organoids in the construction of isogenic disease models and for clinical gene repair.

The bacterial Tight adherence (Tad) secretion system assembles surface pili that drive cell adherence and biofilm formation. Here, authors show the mechanism of assembly for the outer membrane secretin RcpA and how it recruits its pilotin TadD.

An interbacterial toxin that catalyses the deamination of cytidines within double-stranded DNA forms part of a CRISPR-free, RNA-free base editing system that enables manipulation of human mitochondrial DNA.

Wang et al. present a computational framework integrating multi-omics data to infer key schizophrenia risk genes from GWAS data. These genes are predominantly expressed in the developing brain and are enriched for targets of approved drugs.

Several persistent challenges limit the efficacy and applicability of adoptive T cell therapies for cancer, including suboptimal function and/or persistence in vivo, a narrow range of targetable antigens and complex manufacturing processes. This Review discusses the potential of ‘CRISPR 2.0’ precision gene-editing platforms, such as base editing and prime editing to address all of these challenges, and describes the progress made towards clinical translation of these technologies.

While transitions between active and repressive chromatin states are essential for differentiation, little is known regarding their role during development of the brain in Drosophila. Here, the authors investigate the large scale chromatin remodelling taking place during fly neural development.

N₂ reduction to ammonia typically requires transition metal catalysts, proceeding via a strong metal–nitrogen interaction. Now a Ba–Si orthosilicate oxynitride–hydride has been shown to function as a transition-metal-free catalyst for ammonia synthesis through an anion-vacancy-mediated mechanism, where electrons at the vacancy sites facilitate N₂ activation.

An antibody–drug conjugate that targets the pan-haematopoietic marker CD45 combined with transplanted stem cells engineered to be shielded from it can eradicate leukaemic cells while preserving haematopoiesis.

This Review focuses on the potential applications of CRISPR to treat diseases that cannot be overcome by inducing frameshifts or premature stops in coding genes. The authors discuss Cas protein engineering and CRISPR systems beyond Cas9 that create a toolbox to engineer the human genome.

CRISPR base editing technologies can be used for disease modelling. Here the authors use various base editing tools to generate tumour models in human adult stem cell-derived hepatocyte, endometrial and intestinal organoids.

The joint analysis of datasets from NOvA and T2K, the two currently operating long-baseline neutrino oscillation experiments, provides new constraints related to neutrino masses and fundamental symmetries.

Due to the polygenic nature of most diseases, simultaneous correction or introduction of single nucleotide variants is needed. Here, the authors demonstrated the feasibility of multiplex base editing for polygenes disease modeling in cynomolgus monkey embryos with high specificity.