Research Briefing

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  • Identifying substrates of metabolic gene products is important to understand their function in physiology and disease. We developed GeneMAP, a multiomics platform for predicting metabolic gene functions using models of gene expression. We experimentally validated a top-scoring gene–metabolite association, thereby revealing a role for SLC25A48 in mitochondrial choline import.

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  • Idiopathic pulmonary fibrosis (IPF), a deadly lung disease of unclear etiology, lacks sufficient therapeutic options. We extensively mapped the spatial transcriptomes of patient lungs and made translational comparisons with a mouse model of lung fibrosis, providing insights into disease mechanisms and the utility of the animal model for drug discovery.

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  • Relentless accumulation of somatic mutations renders mismatch repair (MMR)-deficient cancers immunogenic. The evolutionary strategies that these hypermutator tumors use to drive immune evasion remain unknown. We identify repetitive homopolymer sequences in MMR genes as genetic ON/OFF switches, which vary mutation rate and bias during tumor evolution to fuel intratumor heterogeneity.

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  • Comprehensive dissection of the transcriptional basis of basal-like differentiation of pancreatic ductal adenocarcinoma (PDAC) revealed MED12 as a core regulator of this abnormal identity. Mechanistic studies demonstrate that MED12 cooperates with the basal-like master regulator transcription factor ΔNp63 by bridging it with the critical Mediator co-activator complex.

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  • We identify an elite haplotype of the transcription factor gene OsGATA8 in rice that is associated with enhanced nitrogen uptake and a higher proportion of productive tillers. Revealing how OsGATA8 regulates nitrogen use efficiency (NUE) enables insights into coordination of nitrogen uptake and productive tiller formation to achieve high NUE in rice.

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  • Microbats utilize ultrasonic echolocation to navigate and locate prey, whereas megabats primarily perceive human-audible sound in daily life. High-quality genomes and single-cell atlases of auditory cortices from microbat and megabat species identify parvalbumin-positive inhibitory neurons and the complexin-1 gene to be crucial in mammalian ultrasound perception.

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  • We used high-throughput transposon screens to examine the responses of generalist and host-adapted Salmonella enterica serovars to 25 stress conditions that recapitulate key stages of human infection. We identified and characterized numerous typhoid-specific gene networks, revealing a role for specific pseudogenes in shaping bacterial fitness outcomes.

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  • Our study explored cell-specific functional consequences and clonal expansions of mosaic structural variants in distinct hematopoietic stem and progenitor cells by utilizing advanced single-cell sequencing techniques. Our single-cell multi-omics approach paves the way for future studies to focus on the roles of somatic structural variants in aging and disease.

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  • An analysis of somatic mutations in blood exomes from 200,618 individuals revealed previously unrecognized genes driving clonal hematopoiesis. Mutations in these genes showed age-dependent clonal expansion and their presence correlated with heightened risks of infection, death and hematological malignancy.

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  • We adapted Tn5 transposition to reduce the amount of input DNA required for amplification-free single-molecule real-time Pacific Biosciences sequencing. We applied transposition-based library preparation in two sensitive methods for concurrently resolving genomes and epigenomes using limiting amounts of native DNA.

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  • Many plant products eaten daily in human diets — such as potato or banana — are polyploid and are notoriously difficult to breed. In this study, the fusion of clonal gametes from distinct diploid tomato parents is used as a blueprint for the design of polyploid genomes in crops.

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  • By developing a modular system for precision epigenome editing, we were able to delineate the causal and quantitative role of chromatin modifications in transcription regulation. The precise effect of chromatin modifications is influenced by multiple contextual factors, including the underlying DNA sequence, transcription factor occupancy and genomic positioning.

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  • We construct a chromosome-level genome assembly of the acorn barnacle Amphibalanus amphitrite. Using this genome together with multi-omics datasets and functional evidence, we reveal the evolution and function of two lineage-specific genes, bcs-6 and bsf, that help A. amphitrite adapt to a sessile lifestyle.

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  • This study establishes in vitro and in vivo systems to study mutagenesis and cancer genome evolution. Using microfluidics and mouse models, the method enables the dissection of co-occurring mutational processes and reveals that acute damage results in mirror-image mutation phasing between sister cells after a single mitosis.

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  • Chromosome-level genome sequences of 69 diverse Arabidopsis thaliana strains reveal a quasi-fixed genome structure worldwide, in which large rearrangement is limited almost exclusively to the centromeric regions. Pan-genome analysis uncovered substantial diversity in gene content that, together with the genome assemblies, will fuel future genetic research.

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  • Using single-cell RNA-sequencing (scRNA-seq) of lung tissue, expression quantitative trait loci (eQTLs) were mapped across 38 cell types, revealing both shared and cell-type-specific effects. Highly cell-type-specific disease-interaction eQTLs were linked to cellular dysregulation in lung disease and lung disease risk variants were connected to their regulatory targets in relevant cell types.

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  • We have curated a comprehensive single-cell reference map of the human breast. Our data explore how age, parity and germline mutations might influence cellular dynamics, revealing unexpected signs of immune exhaustion in healthy tissues from carriers of BRCA1 or BRCA2 germline mutations.

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  • In mice, zygotic genome activation occurs at onset of the two-cell stage in embryonic development and coincides with the exit from totipotency. Our work shows that the transcription factor DUXBL participates in silencing part of the stage-specific two-cell-associated transcriptional program and is required for development to proceed.

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  • We show that in addition to promoter activation, MYC drives cancer progression by activating transcriptional enhancers via a distinct mechanism. MYC cooperates with several other proteins at these cis-regulatory regions to change the epigenome and promote recruitment of RNA polymerase II and enhancer transcription.

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  • Genome-wide CRISPR screening coupled with ATAC-see uncovered modulators that influence global chromatin accessibility. Notably, TFDP1 emerged as a pivotal modulator of chromatin accessibility that acts by controlling histone transcription. Depletion of TFDP1 induced a global elevation in accessibility, enhancing the efficiency of genome editing and iPS cell reprogramming.

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