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AlphaGenome, a deep learning model that inputs 1-Mb DNA sequence to predict functional genomic tracks at single-base resolution across diverse modalities, outperforms existing models in variant effect prediction and enables comprehensive genomic analysis.

Cellular lysine residues can be both methylated and acetylated on the same sidechain to form N^ε-acetyl-N^ε-methyllysine (Kacme), which is found on histone H4 across a range of species and across mammalian tissues and is associated with active chromatin.

A polymer model combining imaging and sequencing suggests how epigenetic remodeling of nanoscale heterochromatin domains regulates gene expression, identifying domain boundaries as critical in controlling cellular behavior in health and disease.

Here the authors perform a gene knockout screen in myeloid cells, identifying 295 genes regulating interleukin-1β production, of which 57 lie in regions associated with inflammatory disease risk. The study sheds light on genetic control of interleukin-1β in inflammation, beyond previously known factors.

Differentiating DCs express ALDH1A2, which produces retinoic acid and suppresses DC activity. Blocking this pathway with a new inhibitor, KyA33, enhances immune responses and boosts the effectiveness of DC cancer vaccines in mouse models.

Chromatin structure is regulated by chemical modifications of histone proteins, but measuring these at single-cell resolution has been challenging. Here, the authors develop a mass spectrometry-based method to profile histone modifications in individual cells, revealing chromatin heterogeneity and differential co-regulation.

A protocol for cryogenic 3D correlative focused ion beam milling using an integrated fluorescence light microscope and montage cryo-ET for nonadherent and adherent mammalian cells, as well as primary Drosophila melanogaster neurons.

Nshanian et al. investigate the differential effects of the short-chain fatty acids propionate and butyrate on chromatin remodelling and gain insight into the mechanisms that drive selective histone acylation.

This study reveals that transcription factors DAF-16/FOXO and HLH-30/TFEB promote healthy aging in C. elegans, in part, by activating lipid metabolism genes that remodel lysosomes into tubular networks.

When lanthanum aluminate and strontium titanate are brought together, a 2D electron gas with many interesting properties forms at the interface. Magnetotransport results obtained by Joshuaet al. suggest that the behaviour of this interface is governed by a small but fundamental set of electronic bands.

Mapping of spatial metabolic gradients in the mouse liver and intestine identifies fructose-induced focal derangements in liver metabolism.

Schwartz and colleagues show that T_H9 cells can respond to bystander cytokines IL-2 and IL-4 to induce antigen-independent expression of IL-9, promoting allergic inflammation. Il9 locus remodeling causes T_H9 cell instability, preventing antigen-independent activation in individuals who are nonallergic. Therapeutic targeting of the STAT5/STAT6 activation cascade may provide relief for patients with chronic allergy.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

Reduced glomerular filtration rate (eGFR) is a hallmark of chronic kidney disease. Here, Pattaro et al. conduct a meta-analysis to discover several new loci associated with variation in eGFR and find that genes associated with eGFR loci often encode proteins potentially related to kidney development.

Directly observing ultrafast single electron dynamics at the atomic scale remains a challenge. Here, the authors demonstrate ultrafast Coulomb blockade at selenium vacancies in WSe2/graphene heterostructures using lightwave-driven scanning tunneling microscopy.

A flexible micro-electrocorticography brain–computer interface that integrates a 256 × 256 array of electrodes, signal processing, data telemetry and wireless powering on a single complementary metal–oxide–semiconductor substrate can provide stable, chronic in vivo recordings.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

Shen et al. report a method for multiplexing isogenic iPSCs for single-cell RNA-seq. With it, they created an atlas of in vitro differentiation and identified TMEM88 as a regulator of cardiovascular development, impacting blood pressure in adult mice.

Here the authors conduct a multi-ancestry meta-analysis of telomere length, used diverse approaches to identify genes underlying association signals, and experimentally validated POP5 and KBTBD6 as regulators of telomere length in human cells.

Understanding how cells differentiate to their final fates is a fundamental biological problem. Here, authors introduce MultiVeloVAE, a probabilistic framework that models gene expression and chromatin accessibility mechanistically, integrates multiple samples, accounts for bifurcations, and enables statistical testing over time.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

Genome-wide analysis identifies variants associated with the volume of seven different subcortical brain regions defined by magnetic resonance imaging. Implicated genes are involved in neurodevelopmental and synaptic signaling pathways.

Here the authors perform a trans expression quantitative trait locus meta-analysis study of over 3,700 people and link a USP18 variant to expression of 50 inflammation genes and lupus risk, highlighting how genetic regulation of immune responses drives autoimmune disease and informs new therapies.

The rapid dissociation of methanetetrol has been suggested as an impediment to its observation, despite the stability of its substituted derivative orthocarbonates. The authors identify methanetetrol as a product of carbon dioxide and water reactions in space-simulation experiments via photoionization mass spectrometry working in tandem with computation quantum chemistry.

An analysis of cell-type diversity in brain samples from a variety of mammalian species, both during development and in adult animals, reveals that the TAC3 initial class of striatal interneurons is conserved across placental mammals and is homologous to Th striatal interneurons in rodents.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

The p53-inducible antiproliferative gene BTG2 is suppressed in many cancers, in the absence of inactivating gene mutations. Here the authors show that the histone lysine methyltransferase SETD1A suppresses the expression of several p53 target genes including BTG2by inducing a network of microRNAs.

Chronic stress is a risk factor for depression, yet the mechanisms are unclear. Here, the authors show in mice that stress drives interferon-mediated neutrophil recruitment from the skull to the brain’s outer membranes, contributing to depressive behaviors.

The mechanisms underlying the activity of non-receptor tyrosine kinase, TNK1, in cancers are unclear. Here the authors show that MARK mediates 14-3-3 and TNK1 interaction which restrains TNK1 activity, while the release of TNK1 from 14-3-3 leads to TNK1 activation through its interaction with ubiquitin and thus results in TNK1-mediated tumor growth in vivo

Analysis of chromatin state and accessibility in mouse tissues from twelve sites and eight developmental stages provides a comprehensive view of chromatin dynamics.

RNA polymerase II is post-translationally modified on its C terminal domain and these modifications have been associated with different states of Pol II transcription. These modifications are now examined at a genome-wide level, and chemical inhibitors are used to argue that promoter-distal Ser7P is specifically placed anew by the Bur1 kinase.

Multimodal DNA methylation and transcriptome profiling of single glioma cells links tumor cell transcriptional states to epigenetics via interaction with PRC2 and shows that these states are heritable and important for tumor plasticity.

Electronic health records are a rich source of clinical data but identifying associations with outcomes is complex. Here, the authors propose a modelling framework ‘InfEHR’ that identifies patient trajectories in electronic health records and generates a likelihood for clinical phenotypes.

This overview of the ENCODE project outlines the data accumulated so far, revealing that 80% of the human genome now has at least one biochemical function assigned to it; the newly identified functional elements should aid the interpretation of results of genome-wide association studies, as many correspond to sites of association with human disease.

Multiancestry genome-wide association analyses identify new risk loci for stroke and stroke subtypes. Fine mapping and bioinformatics analyses of these risk loci point to mechanisms not previously implicated in stroke pathophysiology.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

Enhanced polyamine depletion in neuroblastoma models decreases translation of mRNA codons with adenosine in the third position, reprogramming the tumour proteome away from cell cycle progression and towards differentiation.

Li-Fraumeni syndrome leads to an increased predisposition to tumour development. Here, the authors develop a support vector machine model to predict early cancer risk in individuals using peripheral blood DNA methylation profiles.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

The authors describe an integrated atlas of the diverse cell types in the mouse primary motor cortex.

Somatically determined preferential allelic expression of select genes that when mutated cause inborn errors of immunity corresponds with disease phenotypes, suggesting that the penetrance and expressivity of monogenic disorders is also dependent on the ‘transcriptotype’.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.

Kodali, Proietti et al. report that increased numbers of P-bodies in leukaemia cells account for sequestration and prevention of tumour-suppressive mRNAs from being translated, which could be targeted as a potential intervention in myeloid leukaemia.

The ability to measure strain in cells and tissues in vitro with minimal perturbation and at high spatial resolution has proven challenging. Here the authors develop a fluorescently-labelled fibronectin square lattice mesh that can be applied to the surface of cells and tissues to enable direct quantification and mapping of strain over time.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Newman et al. show that, upon mitochondrial DNA (mtDNA) replication stress, enlarged nucleoids are trafficked to endosomes. Endosomal rupture releases mtDNA into the cytoplasm, triggering cGAS–STING activation and innate immune signalling.

White matter hyperintensities (WMH) are a common brain-imaging feature of cerebral small vessel disease. Here, the authors carry out a GWAS and followup analyses for WMH-volume, implicating several variants with potential for risk stratification and drug targeting.

In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. Here they show that perichondrial cells are destined to become adipocyte-biased stromal cells, indicating that marrow stromal compartments are defined by their cells of origin.