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MKL1 is a key transcriptional co-activator of actin cytoskeleton genes. Here the authors show that MKL1 activation in somatic cells reduces chromatin accessibility and hinders full reprogramming to pluripotency. Reduction of MKL1, disruption of actin cytoskeleton and its links to the nucleus relieve this repression.

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.

Nematode signals such as ascarosides are sensed by G protein-coupled receptors of a nematode-trapping fungus, resulting in fungal activation of cAMP–PKA signalling and trap development.

Some cancer patients first present with metastases where the location of the primary is unidentified; these are difficult to treat. In this study, using machine learning, the authors develop a method to determine the tissue of origin of a cancer based on whole sequencing data.

Simultaneous profiling of the genome, methylome, epigenome and transcriptome using single-molecule chromatin fiber sequencing and multiplexed arrays isoform sequencing identifies the genetic and molecular basis of an undiagnosed Mendelian disease case with an X;13-balanced translocation.

The assembly of the genome of the koala provides insights into its adaptive biology and identifies gene expansions that contribute to its ability to detoxify eucalyptus-derived compounds and perceive plant secondary metabolites.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

In photosynthesis the oxidation of water is a requirement for providing sufficient protons and electrons for fuel formation. A biphasic water splitting catalyst tailored for integration with high-performance semiconductor photoanodes is now reported.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

The human embryonic kidney 293 (HEK293) cell lineage is widely used in cell biology and biotechnology. Here, the authors apply whole genome resequencing methods to characterise genomic variation in six HEK293 cell lines and suggest that this variation could affect experiments using these cell lines.

A high-throughput screen identified a small molecule that promoted inclusion of SMN2 exon 7, increased SMN2 protein levels and extended survival in a SMA mouse model through stabilization of the interaction between SMN2 pre-mRNA and U1 snRNP complex.

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution.

Watson et al. demonstrate that astrocyte mitochondria can be horizontally transferred to glioblastoma cells in a GAP43-dependent manner, leading to changes in mitochondrial respiration and metabolism that promote proliferation and tumor growth.

DoTA-seq leverages a microfluidic droplet system to isolate and lyse diverse microbes and amplify target genetic loci, enabling high-throughput single-cell sequencing of microbial populations.

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants.

A survey of T cell repertoire evolution in the tumors, healthy tissue and blood of patients with early-stage untreated lung cancer offers an opportunity to monitor and identify neoantigen-specific T cells for personalized immunotherapy.

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.

In a GWAS study of 32,438 adults, the authors discovered five novel loci for intracranial volume and confirmed two known signals. Variants for intracranial volume were also related to childhood and adult cognitive function and to Parkinson's disease, and enriched near genes involved in growth pathways, including PI3K-AKT signaling.

Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

DeepGlioma, a multimodal deep learning approach for intraoperative diagnostic screening of diffuse glioma, trained on stimulated Raman histology and large-scale public genomic data, can predict molecular alterations for diffuse glioma diagnosis with high accuracy.

Cryo-electron microscopy studies show that dynamic coordination of Na⁺ in the ion channel of Dispatched homologue 1 and the transmembrane Na⁺ gradient have key roles in exporting lipid-modified Hedgehog protein signal.

Sexual interactions with males shorten the lifespan of the opposite sex in several species, including Caenorhabditis elegans, but the mechanisms are not fully understood. Here the authors use transcriptomic profiling in C. elegans to systematically identify the genetic pathways involved in male-induced demise, which include upregulation of a conserved ion channel that regulates fat metabolism.

Koplev et al. apply interactive system analyses to infer and characterize gene-regulatory networks (GRNs) active within and across tissues that cause cardiometabolic disease and coronary artery disease (CAD). By including GWAS in the integrative analysis, the provided multiorgan framework of GRNs is suggested to explain significantly more heritability of CAD than what has been achieved by analyzing GWAS alone.

Necrotizing Enterocolitis (NEC) is an untreatable intestinal disease in infants. Here the authors show that human and experimental mouse NEC is associated with altered toll-like receptor expression in the intestine, enhanced Th17/type 3 polarization in adaptive immune and innate lymphoid cells, dysregulated microbiota, and reduced interleukin-37 signaling.

The next step after sequencing a genome is to figure out how the cell actually uses it as an instruction manual. A large international consortium has examined 1% of the genome for what part is transcribed, where proteins are bound, what the chromatin structure looks like, and how the sequence compares to that of other organisms.

Relapsed pediatric acute myeloid leukemia is associated with poor prognosis. Here, the authors use RNA-seq data from 1503 primary samples to create a combined transcriptional and cytomolecular signature to improve relapse risk prediction.

Weaver and colleagues use breast cancer patient-derived organoids and mouse models to find an inhibitory role for the nuclear repressor NCOR2 in chemotherapy response and antitumor immunity, which can be targeted by blocking NCOR2–HDAC3 interaction.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

Tumor-associated macrophages support an immunosuppressive tumor microenvironment. Di Conza et al. uncover how IRE1–XBP1 and IRE1−STAT3 endoplasmic reticulum stress responses pathways are engaged by tumor-derived lipids to orchestrate pro-tumorigenic features and survival in tumor-associated macrophages.

The genetic changes that occur in late stage metastatic melanoma are not well delineated. Here, the authors use rapid autopsy samples from metastatic melanoma patients and show that the late stage in the disease is characterised by whole genome doubling and aneuploidy.

Homozygous deletions are rare in cancers and often target tumour suppressor genes. Here, the authors conduct pan-cancer analyses and apply statistical modelling to identify 27 candidate tumour suppressors, including MAFTRR, KIAA1551, and IGF2BP2.

Neural stem and progenitor cells (NSPCs) encounter constant stresses during aging, such as elevated oxidative stress. Here the authors show that oxidative stress induced reduction in NSPC neural differentiation is mediated by a FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signalling cascade initiated by FOXO3 oxidation.

Deep-learning models for the automated measurement of retinal-vessel calibre in retinal photographs perform comparably to or better than expert graders in associations of measurements of retinal-vessel calibre with cardiovascular risk factors.

The hydroxylase EgIN2 contributes to triple negative breast cancers. Here, using an enzyme-substrate trapping strategy, the authors identify ASDL as a bona fide substrate of EgIN2 promoting aggressive properties of TNBC via the activation of cMYC signaling.

Whole-genome sequencing analysis of individuals with primary immunodeficiency identifies new candidate disease-associated genes and shows how the interplay between genetic variants can explain the variable penetrance and complexity of the disease.

Diffuse Intrinsic Pontine Gliomas are diagnosed by sampling a small portion of the tumour. Here, using multiple samples from tumours, the authors analyse the spatial and temporal distribution of driver mutations revealing that H3K27M mutations arise first in tumorigenesis followed by a specific invariable sequence of driver mutations, which are homogeneously distributed across the tumour mass.

Alison Dunning, Stacey Edwards and colleagues analyze 3,872 common variants across the ESR1 locus in 118,816 women. They find five independent variants within regulatory regions that associate with different breast cancer–related phenotypes and regulate the expression of ESR1, RMND1 and CCDC170.

Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.

The capacity for thermoregulation deteriorates with age, particularly in cold environments. Here the authors demonstrate inDrosophilathat age-related changes in cold avoidance result from a shift in the relative contribution of two parallel mushroom body circuits that are modulated by dopamine.

Chronic Hepatitis C infection is associated with a broad spectrum of liver pathologies, ranging from inflammation to fibrosis and liver cancer. Here Thabet et al. identified a polymorphism in the gene MBOAT7 that is associated with increased hepatic inflammation and higher risk of fibrosis development and progression.

The crystal structures of the histone chaperone DAXX histone-binding domain bound to a histone H3.3–H4 dimer are described; DAXX wraps around the H3.3–H4 dimer and alters its conformation.

Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.

The UCLA Ribonomics group reports that the nuclear export efficiency of innate immune mRNAs varies over a hundred-fold range such that for many genes only a small fraction of the newly synthesized premRNA reaches the cytoplasm. They show that nuclear export and cytoplasmic decay rates are correlated thereby ensuring similar expression levels of short-lived and long-lived mRNAs.

ENCODE is a resource comprising thousands of functional genomic datasets. Here, the authors present custom annotation within ENCODE for cancer, highlighting a workflow that can help prioritise key elements in oncogenesis.

Draft genome, 994 re-sequenced lines and GWAS for yield-traits provide a resource of genetics and genomics tools for pearl millet researchers and breeders.

Human ALS/FTD patient iPSC-derived neurons are used to uncover mechanisms by which C9ORF72 mutations cause neurodegeneration.

HDX–MS analysis reveals the SARS-CoV-2 spike ectodomain reversibly samples an open-trimer conformation that reveals epitopes for a pan-coronavirus antibody; interconversion with the prefusion conformation is modulated by temperature, ACE2 receptor binding, and sequence variants.