Biayna, Baranovskii and colleagues report that intron-retained RNAs derived from cell cycle- and genome maintenance-related genes are pooled at the periphery of nuclear speckles and undergo synchronou...

a, Schematic of different strategies tested for CRISPR-mediated DNA insertions at single nicks, including nCas9/sgRNA with unlabeled dsDNA donors (nCas9), nCas9/sgRNA with unlabeled dsDNA donors under NHEJ inhibitor treatment, hRAD51*-nCas9/sgRNA with unlabeled dsDNA donors, or nCas9-mSA/sgRNA with biotinylated donors, respectively. hRAD51* refers to the RAD51 S208E and A209D mutant. Related to Fig. 1a–c. b, Relative insertion efficiency of different systems (nCas9, nCas9 under M3814, AZD-7648, NU7441 and NU7026 treatment, respectively) for inserting EGFP-P2A sequences at the ACTB locus, normalized to control (Ctrl): HEK293T cells treated with nCas9 and sgACTB under DMSO treatment. Related to Fig. 1a strategy (2). c, Schematic of additional strategies tested. Related to Fig. 1d–f. d, Representative confocal images of HEK293T cells 14 days after transfection of the nCas9, KNIT editor 1 (KE1), Cas9 or paired nickases systems for EGFP-P2A insertion at the ACTB locus, respectively. Experiments were replicated independently three times. Scale bars, 50 μm. e,f, Long-term stability of EGFP expression (e) and representative flow cytometry analysis (f) of HEK293T cells after inserting EGFP-P2A into the ACTB locus using Cas9 and KE1 on day 14 and 54 after transfection. g, Schematic of HTS library preparation for quantifying the indel rates in uninserted alleles using nested PCR...

Below the scale of long-range compartments and topologically associating domains (TADs) lie a diverse set of local chromatin organization features. Recent maps and single-molecule assays reveal modula...

Targeted protein degradation offers a way to test drug targets before costly drug development begins. Here, the authors benchmark tag-degrader systems in mice, identify dTAG as the most effective appr...

This Review presents the formation of large extracellular vesicle (L-EV) subsets, highlighting that their contents and physiological relevance, for example, in intercellular communication, are driven ...

Accurate selection of start codons by ribosomes is a fundamental determinant of proteome composition. Although the 'Kozak sequence'—an 8-nucleotide sequence flanking the start codon—has long been viewed as the primary determinant of initiation in eukaryotes, it fails to explain the large diversity of start codon usage across transcripts. Here we combine massively parallel reporter assays, bioinformatics, machine learning, single-molecule imaging and cryo-electron microscopy to define the 'extended translation initiation sequence (eTIS)', an ~80-nucleotide sequence surrounding the start codon that governs initiation efficiency. A deep-learning model trained on eTIS features accurately predicts translation initiation across transcripts. Unexpectedly, we find that the Kozak sequence is not optimal for initiation as is widely presumed, and we identify the origin of this discrepancy. eTIS nucleotides that promote efficient initiation are enriched in the human transcriptome and are evolutionarily conserved, underscoring their functional importance. Biophysical and structural analyses reveal that specific eTIS residues—including the key +6 position and residues in the mRNA entry and exit channel—engage ribosomal proteins, rRNA and initiation factors to promote start codon recognition by stabilizing the ribosome at the start codon and facilitating the structural transitions required for initiation. Finally, optimization of the eTIS markedly enhances translational fidelity and protein output from therapeutic mRNAs, highlighting its practical utility. Together, these findings redefine the sequence logic of translation initiation and establish a framework for precise control of protein expression. ### Competing Interest Statement The authors have declared no competing interest.

Nature Reviews Genetics, Published online: 05 May 2026; doi:10.1038/s41576-026-00965-zIn this Journal Club article, Qiupeng Lin recalls the 2019 paper by Anzalone et al. that introduced prime editing, and reflects on the impact of this technology on genome biology and beyond.

DNA is wrapped around histones, forming chromatin, which becomes more compact during mitosis. Kochanova et al. elucidate the complex landscape of histone post-translational modifications upon mitotic chromosome formation and discover that H3T3ph is restricted to chromatin with silent genes and that acetylation is only mildly decreased as chromosomes form.

In this Review, Zhu et al. outline the various CRISPR-based tools recently built for dynamic DNA and RNA imaging, which have provided insights into various molecular mechanisms. The authors also discu...

Chen et al. engineer TRANSFER (trogocytosis-inspired receptor transfer and functional effector release), a method to deliver functional cargos from donor to recipient cells in a specific manner via di...

Nature Reviews Genetics, Published online: 09 March 2026; doi:10.1038/s41576-026-00939-1In this Perspective, Maizels and Briscoe discuss the limitations of current models of gene regulatory networks and outline solutions to harness data abundance without compromising explanatory power.

Understanding how cells make decisions over time requires the ability to link past molecular states to future phenotypic outcomes. We present TimeVault, a genetically encoded system that records and s...

Recombinases generated by phage-assisted evolution enhance the efficiency of the prime-editing-assisted targeted integration of large genes in mammalian cells.

In this issue of Molecular Cell, Song et al. focus on the regulation of hypoxia-induced alternative splicing (AS) in cancer cells and provide evidence for key regulatory roles for MALAT1-SRSF1 condensates in preferential pre-mRNA binding and RNAPII recruitment.

Analyses of liver biopsies from a child with spinal muscular atrophy treated with adeno-associated virus gene therapy who developed hepatitis reveal contaminating manufacturing plasmids and disrupted ...

INSTALL overcomes fundamental challenges for DNA delivery and integration methods by synergizing immune-stealth nucleic acids with recombinases to enable kilobase-scale integration strategies without ...

Nature Reviews Genetics, Published online: 17 February 2026; doi:10.1038/s41576-026-00937-3In this Review, Ji et al. overview how rapidly advancing experimental and computational methods are enabling improved and automated annotation of gene structure and function, providing researchers with genome annotation resources of unprecedented scale and resolution.

Nature Protocols, Published online: 16 January 2026; doi:10.1038/s41596-025-01285-yWe present a protocol for high-resolution genome-wide mapping of nascent RNA polymerase II transcription initiation of both stable RNAs and transiently expressed RNAs using total RNA from diverse sample types.

Nature Reviews Genetics, Published online: 15 January 2026; doi:10.1038/s41576-025-00928-wAlternative 3′-end processing of nascent RNA, known as alternative polyadenylation (APA), increases transcript diversity and augments post-transcriptional modulation of gene expression. APA profiles are highly dynamic in response to cell growth, differentiation and extracellular cues, and dysregulated APA is a hallmark of human diseases.

Engineered repressible promoters enable tunable fluorescence outputs in Bacteroides and the development of biosensors that report on subclinical gut malabsorption.

Dierks and Schwartz discuss the m6A surveillance model, proposing that m6A flags “undesirable” intron-less RNAs (e.g., transposons) for decay. This provides a mechanism to distinguish “legitimate” spliced mRNAs and potentially suppress harmful RNA.

Lin et al. introduce AAVLINK, a robust gene delivery platform that surpasses the traditional packaging limits of adeno-associated viruses (AAVs). This system enables efficient delivery of large therapeutic genes and CRISPR components, offering promising avenues for treating genetic disorders such as Dravet syndrome and Phelan-McDermid syndrome.

Nature Reviews Cardiology, Published online: 22 January 2026; doi:10.1038/s41569-026-01253-3In this Review, Ferrucci and colleagues propose that inflammation is a resilience mechanism that resolves molecular and cellular damage driven by environmental stressors. With ageing, however, this protective response can become dysregulated and maladaptive, promoting collateral changes central to the pathophysiology of cardiovascular disease.

The vaccines are tailor-made to target each patient's unique cancer.

Kathiriya et al. identify a cardiac progenitor lineage with expression of Tbx5 and anterior heart field-specific expression of Mef2c that bisects the intraventricular septum during development and sho...

Nature Reviews Genetics, Published online: 13 January 2025; doi:10.1038/s41576-024-00807-wEpigenetic clocks based on DNA methylation data are machine learning tools used to estimate chronological and biological age. The authors review computational and…

Classifying chromatin loops from 3D genomics data according to their epigenetic and structural attributes is important for inferring their functional roles. Currently, such classification typically relies on the manual intersection of epigenomic signal peaks and loop anchor locations. To automate this, remove peak-calling biases and include information inherent to 3D genomics signal structure, we developed LoopBin, a framework based on a variational deep embedding (VaDE) neural network. We applied LoopBin to kilobase-resolution Micro-C data and segmented tens of thousands of loops into clusters with distinct features using minimal histone modification and transcription factor-binding data. These features were indicative of apparently distinct biological function by each subgroup of loops. Therefore, LoopBin can provide insights into the dynamic shifts in loop classification that can occur upon perturbation of cell homeostasis or signaling. ### Competing Interest Statement The authors have declared no competing interest.

Endo et al. show that preserving the intestinal niche enables near-complete engraftment of ileal organoids in the jejunum. The resulting ilealized segment restores bile acid absorption and improves survival in short bowel syndrome, suggesting a path toward region-targeted, autologous regenerative therapy.

Germany is one of the most popular destinations for students and scholars worldwide, but those pursuing academic careers face significant hurdles to success.

High-throughput chromosome conformation capture (Hi-C) is a powerful tool to investigate 3D genome architecture. Here, we present a protocol for preparing low-input Hi-C libraries from mitotic cells isolated by fluorescence-activated cell sorting (FACS) to study chromatin conformation in mitotic cells. We describe steps for mitotic arrest, harvest and fixation of cultured cells, staining with an anti-Mitotic Protein Marker (MPM2), and isolation of mitotic cells. We then detail procedures for qua...

There is great interest in modeling human HFpEF in animals to identify underlying mechanisms and ultimately improve sorely needed therapies. Our current models are a step forward but still fall short ...

A gene-editing approach enables modification of bacteria within the mouse gut

Wang et al. establish an in vivo proteomic labeling (IVPL) system combining the Btn-Ph-3F substrate with APEX2-EGFPf/f Cre crosses to map cell-type-specific proteomes in intact organs and trace patient-derived exosomal proteins. IVPL identifies LDHAL6A as a pro-metastatic driver and highlights its potential as a therapeutic target in TNBC.

Nature Reviews Genetics, Published online: 10 November 2025; doi:10.1038/s41576-025-00913-3In this Tools of the Trade article, Shaoqian Ma discusses scFLUENT-seq, a method that enables quantitative, genome-wide analysis of nascent transcription in single cells.