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Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics. [Display omitted] • EN-TEx includes 1,635 datasets mapped to 4 personal genomes, ∼30 tissues × ∼15 assays • Comprehensive catalog of allele-specific activity, decorating regulatory elements • Model to transfer known eQTLs to difficult-to-profile tissues (e.g., skin→heart) • Transformer model for predicting allelic activity based on local sequence context Understanding the impact of genetic variants is important to functional genomics. EN-TEx provides epigenomes across tissues, coupled with long-read genome assemblies, to build generalizable models of variant impact. [ABSTRACT FROM AUTHOR]

Summary: Differences in chromatin organization are key to the multiplicity of cell states that arise from a single genetic background, yet the landscapes of in vivo tissues remain largely uncharted. Here, we mapped chromatin genome-wide in a large and diverse collection of human tissues and stem cells. The maps yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments. They also reveal global features of the epigenome, related to nuclear architecture, that also vary across cellular phenotypes. Specifically, developmental specification is accompanied by progressive chromatin restriction as the default state transitions from dynamic remodeling to generalized compaction. Exposure to serum in vitro triggers a distinct transition that involves de novo establishment of domains with features of constitutive heterochromatin. We describe how these global chromatin state transitions relate to chromosome and nuclear architecture, and discuss their implications for lineage fidelity, cellular senescence, and reprogramming. [Copyright &y& Elsevier]

Summary: Hundreds of chromatin regulators (CRs) control chromatin structure and function by catalyzing and binding histone modifications, yet the rules governing these key processes remain obscure. Here, we present a systematic approach to infer CR function. We developed ChIP-string, a meso-scale assay that combines chromatin immunoprecipitation with a signature readout of 487 representative loci. We applied ChIP-string to screen 145 antibodies, thereby identifying effective reagents, which we used to map the genome-wide binding of 29 CRs in two cell types. We found that specific combinations of CRs colocalize in characteristic patterns at distinct chromatin environments, at genes of coherent functions, and at distal regulatory elements. When comparing between cell types, CRs redistribute to different loci but maintain their modular and combinatorial associations. Our work provides a multiplex method that substantially enhances the ability to monitor CR binding, presents a large resource of CR maps, and reveals common principles for combinatorial CR function. [ABSTRACT FROM AUTHOR]

Widespread changes to DNA methylation and chromatin are well documented in cancer, but the fate of higher-order chromosomal structure remains obscure. Here we integrated topological maps for colon tumors and normal colons with epigenetic, transcriptional, and imaging data to characterize alterations to chromatin loops, topologically associated domains, and large-scale compartments. We found that spatial partitioning of the open and closed genome compartments is profoundly compromised in tumors. This reorganization is accompanied by compartment-specific hypomethylation and chromatin changes. Additionally, we identify a compartment at the interface between the canonical A and B compartments that is reorganized in tumors. Remarkably, similar shifts were evident in non-malignant cells that have accumulated excess divisions. Our analyses suggest that these topological changes repress stemness and invasion programs while inducing anti-tumor immunity genes and may therefore restrain malignant progression. Our findings call into question the conventional view that tumor-associated epigenomic alterations are primarily oncogenic. • Hierarchical layers of nuclear architecture are altered in colorectal tumors • An intermediate genome compartment is defined in primary tissues • Compartmental reorganization and hypomethylation occur in tumors and aging cells • Reorganization is associated with tumor-suppressive transcriptional programs Integrated analyses of genome topological, epigenetic, and transcriptional features of colorectal tumors highlight substantial genome compartmental reorganization associated with tumor-suppressive rather than oncogenic transcriptional outcomes. [ABSTRACT FROM AUTHOR]

Summary Genome-wide association studies (GWASs) implicate the PHACTR1 locus (6p24) in risk for five vascular diseases, including coronary artery disease, migraine headache, cervical artery dissection, fibromuscular dysplasia, and hypertension. Through genetic fine mapping, we prioritized rs9349379, a common SNP in the third intron of the PHACTR1 gene, as the putative causal variant. Epigenomic data from human tissue revealed an enhancer signature at rs9349379 exclusively in aorta, suggesting a regulatory function for this SNP in the vasculature. CRISPR-edited stem cell-derived endothelial cells demonstrate rs9349379 regulates expression of endothelin 1 ( EDN1 ), a gene located 600 kb upstream of PHACTR1 . The known physiologic effects of EDN1 on the vasculature may explain the pattern of risk for the five associated diseases. Overall, these data illustrate the integration of genetic, phenotypic, and epigenetic analysis to identify the biologic mechanism by which a common, non-coding variant can distally regulate a gene and contribute to the pathogenesis of multiple vascular diseases. [ABSTRACT FROM AUTHOR]

Antibiotic tolerance and persistence are often associated with treatment failure and relapse, yet are poorly characterized. In distinction from resistance, which is measured using the minimum inhibitory concentration metric, tolerance and persistence values are not currently evaluated in the clinical setting, and so are overlooked when a course of treatment is prescribed. In this article, we introduce a metric and an automated experimental framework for measuring tolerance and persistence. The tolerance metric is the minimum duration for killing 99% of the population, MDK 99 , which can be evaluated by a statistical analysis of measurements performed manually or using a robotic system. We demonstrate the technique on strains of Escherichia coli with various tolerance levels. We hope that this, to our knowledge, new approach will be used, along with the existing minimum inhibitory concentration, as a standard for the in vitro characterization of sensitivity to antimicrobials. Quantification of tolerance and persistence may provide vital information in healthcare, and aid research in the field., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)