4,572 results match your criteria Genome Research [Journal]


New guidelines for DNA methylome studies regarding 5-hydroxymethylcytosine for understanding transcriptional regulation.

Genome Res 2019 Feb 19. Epub 2019 Feb 19.

The Chinese University of Hong Kong

Many DNA methylome profiling methods cannot distinguish between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Since 5mC typically acts as a repressive mark whereas 5hmC is an intermediate form during active demethylation, the inability to separate their signals could lead to incorrect interpretation of the data. Is the extra information contained in 5hmC signals worth the additional experimental and computational costs? Here we combine whole-genome bisulfite sequencing (WGBS) and oxidative WGBS (oxWGBS) data in various human tissues to investigate the quantitative relationships between gene expression and the two forms of DNA methylation at promoters, transcript bodies, and immediate downstream regions. Read More

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http://dx.doi.org/10.1101/gr.240036.118DOI Listing
February 2019

Improved discovery of genetic interactions using CRISPRiSeq across multiple environments.

Genome Res 2019 Feb 19. Epub 2019 Feb 19.

Stanford University;

Large-scale Genetic Interaction (GI) screens in yeast have been invaluable for our understanding of molecular systems biology, and for characterizing novel gene function. Due in part to the high costs and long experiment times required, a preponderance of GI data has been generated in a single environmental condition. However, an unknown fraction of GIs may be specific to other conditions. Read More

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http://dx.doi.org/10.1101/gr.246603.118DOI Listing
February 2019

Ribosomal DNA harbors an evolutionarily conserved clock of biological aging.

Genome Res 2019 Feb 14. Epub 2019 Feb 14.

Department of Environmental Health, Program in Molecular and Integrative Physiological Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.

The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, , and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.241745.118
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http://dx.doi.org/10.1101/gr.241745.118DOI Listing
February 2019
7 Reads

Dynamics of cardiomyocyte transcriptome and chromatin landscape demarcates key events of heart development.

Genome Res 2019 Feb 13. Epub 2019 Feb 13.

International Institute of Molecular and Cell Biology in Warsaw, Laboratory of Zebrafish Developmental Genomics, 02-109 Warsaw, Poland.

Organogenesis involves dynamic regulation of gene transcription and complex multipathway interactions. Despite our knowledge of key factors regulating various steps of heart morphogenesis, considerable challenges in understanding its mechanism still exist because little is known about their downstream targets and interactive regulatory network. To better understand transcriptional regulatory mechanism driving heart development and the consequences of its disruption in vivo, we performed time-series analyses of the transcriptome and genome-wide chromatin accessibility in isolated cardiomyocytes (CMs) from wild-type zebrafish embryos at developmental stages corresponding to heart tube morphogenesis, looping, and maturation. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.244491.118
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http://dx.doi.org/10.1101/gr.244491.118DOI Listing
February 2019
1 Read

Evolution of gene regulation in ruminants differs between evolutionary breakpoint regions and homologous synteny blocks.

Genome Res 2019 Feb 13. Epub 2019 Feb 13.

Royal Veterinary College;

The role of chromosome rearrangements in driving evolution has been a long-standing question of evolutionary biology. Here we focused on ruminants as a model to assess how rearrangements may have contributed to the evolution of gene regulation. Using reconstructed ancestral karyotypes of Cetartiodactyls, Ruminants, Pecorans, and Bovids, we traced patterns of gross chromosome changes. Read More

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http://dx.doi.org/10.1101/gr.239863.118DOI Listing
February 2019

Comprehensive, integrated, and phased whole-genome analysis of the primary ENCODE cell line K562.

Genome Res 2019 Feb 8. Epub 2019 Feb 8.

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.

K562 is widely used in biomedical research. It is one of three tier-one cell lines of ENCODE and also most commonly used for large-scale CRISPR/Cas9 screens. Although its functional genomic and epigenomic characteristics have been extensively studied, its genome sequence and genomic structural features have never been comprehensively analyzed. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.234948.118
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http://dx.doi.org/10.1101/gr.234948.118DOI Listing
February 2019
1 Read

Mapping global and local coevolution across 600 species to identify novel homologous recombination repair genes.

Genome Res 2019 Feb 4. Epub 2019 Feb 4.

Department of Developmental Biology and Cancer Research, Institute for Medical Research-Israel-Canada, Hebrew University of Jerusalem, Jerusalem 91120, Israel.

The homologous recombination repair (HRR) pathway repairs DNA double-strand breaks in an error-free manner. Mutations in HRR genes can result in increased mutation rate and genomic rearrangements, and are associated with numerous genetic disorders and cancer. Despite intensive research, the HRR pathway is not yet fully mapped. Read More

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http://dx.doi.org/10.1101/gr.241414.118DOI Listing
February 2019

CG dinucleotides enhance promoter activity independent of DNA methylation.

Genome Res 2019 Feb 1. Epub 2019 Feb 1.

Friedrich Miescher Institute;

Most mammalian RNA Polymerase II initiation events occur at CpG islands, which are rich in CpGs and devoid of DNA methylation. Despite their relevance for gene regulation, it is unknown to what extent the CpG dinucleotide itself actually contributes to promoter activity. To address this question, we determined the transcriptional activity of a large number of chromosomally integrated promoter constructs and monitored binding of transcription factors assumed to play a role in CpG island activity. Read More

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http://dx.doi.org/10.1101/gr.241653.118DOI Listing
February 2019
1 Read

Chromatin architecture reorganisation during neuronal cell differentiation in Drosophila genome.

Genome Res 2019 Feb 1. Epub 2019 Feb 1.

University of Essex

The organization of the genome into topologically associating domains (TADs) was shown to have a regulatory role in development and cellular functioning, but the mechanism involved in TAD establishment is still unclear. Here, we presented the first high-resolution contact map of Drosophila neuronal cells (BG3) and identified different classes of TADs by comparing this to genome organization in embryonic cells (Kc167). We find that only some TADs are conserved in both cell lines, whereas the rest are cell-specific TADs. Read More

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http://dx.doi.org/10.1101/gr.246710.118DOI Listing
February 2019

Leveraging chromatin accessibility for transcriptional regulatory network inference in T Helper 17 Cells.

Genome Res 2019 Jan 29. Epub 2019 Jan 29.

Center for Computational Biology, Flatiron Institute, New York, New York 10010, USA.

Transcriptional regulatory networks (TRNs) provide insight into cellular behavior by describing interactions between transcription factors (TFs) and their gene targets. The assay for transposase-accessible chromatin (ATAC)-seq, coupled with TF motif analysis, provides indirect evidence of chromatin binding for hundreds of TFs genome-wide. Here, we propose methods for TRN inference in a mammalian setting, using ATAC-seq data to improve gene expression modeling. Read More

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http://dx.doi.org/10.1101/gr.238253.118DOI Listing
January 2019

The circular RNome of primary breast cancer.

Genome Res 2019 Jan 28. Epub 2019 Jan 28.

Erasmus MC Cancer Institute and Cancer Genomics Netherlands, University Medical Center Rotterdam, Department of Medical Oncology, 3015GD Rotterdam, the Netherlands.

Circular RNAs (circRNAs) are a class of RNAs that is under increasing scrutiny, although their functional roles are debated. We analyzed RNA-seq data of 348 primary breast cancers and developed a method to identify circRNAs that does not rely on unmapped reads or known splice junctions. We identified 95,843 circRNAs, of which 20,441 were found recurrently. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.238121.118
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http://dx.doi.org/10.1101/gr.238121.118DOI Listing
January 2019
5 Reads

Single-cell sequencing of primate preimplantation embryos reveals chromosome elimination via cellular fragmentation and blastomere exclusion.

Genome Res 2019 Jan 25. Epub 2019 Jan 25.

Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon 97006, USA.

Aneuploidy that arises during meiosis and/or mitosis is a major contributor to early embryo loss. We previously showed that human preimplantation embryos encapsulate missegregated chromosomes into micronuclei while undergoing cellular fragmentation and that fragments can contain chromosomal material, but the source of this DNA was unknown. Here, we leveraged the use of a nonhuman primate model and single-cell DNA-sequencing (scDNA-seq) to examine the chromosomal content of 471 individual samples comprising 254 blastomeres, 42 polar bodies, and 175 cellular fragments from a large number ( = 50) of disassembled rhesus cleavage-stage embryos. Read More

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http://dx.doi.org/10.1101/gr.239830.118DOI Listing
January 2019

High-throughput functional analysis of lncRNA core promoters elucidates rules governing tissue specificity.

Genome Res 2019 Jan 25. Epub 2019 Jan 25.

Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA.

Transcription initiates at both coding and noncoding genomic elements, including mRNA and long noncoding RNA (lncRNA) core promoters and enhancer RNAs (eRNAs). However, each class has a different expression profile with lncRNAs and eRNAs being the most tissue specific. How these complex differences in expression profiles and tissue specificities are encoded in a single DNA sequence remains unresolved. Read More

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http://dx.doi.org/10.1101/gr.242222.118DOI Listing
January 2019
1 Read

Contrasting roles of the RSC and ISW1/CHD1 chromatin remodelers in RNA polymerase II elongation and termination.

Genome Res 2019 Jan 25. Epub 2019 Jan 25.

Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

Most yeast genes have a nucleosome-depleted region (NDR) at the promoter and an array of regularly spaced nucleosomes phased relative to the transcription start site. We have examined the interplay between RSC (a conserved essential SWI/SNF-type complex that determines NDR size) and the ISW1, CHD1, and ISW2 nucleosome spacing enzymes in chromatin organization and transcription, using isogenic strains lacking all combinations of these enzymes. The contributions of these remodelers to chromatin organization are largely combinatorial, distinct, and nonredundant, supporting a model in which the +1 nucleosome is positioned by RSC and then used as a reference nucleosome by the spacing enzymes. Read More

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http://dx.doi.org/10.1101/gr.242032.118DOI Listing
January 2019
1 Read

A chromosome-scale assembly of the axolotl genome.

Genome Res 2019 02 24;29(2):317-324. Epub 2019 Jan 24.

Department of Neuroscience, University of Kentucky, Lexington, Kentucky 40506, USA.

The axolotl () provides critical models for studying regeneration, evolution, and development. However, its large genome (∼32 Gb) presents a formidable barrier to genetic analyses. Recent efforts have yielded genome assemblies consisting of thousands of unordered scaffolds that resolve gene structures, but do not yet permit large-scale analyses of genome structure and function. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.241901.118
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http://dx.doi.org/10.1101/gr.241901.118DOI Listing
February 2019
3 Reads

Fast and flexible bacterial genomic epidemiology with PopPUNK.

Genome Res 2019 02 24;29(2):304-316. Epub 2019 Jan 24.

MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London W2 1PG, United Kingdom.

The routine use of genomics for disease surveillance provides the opportunity for high-resolution bacterial epidemiology. Current whole-genome clustering and multilocus typing approaches do not fully exploit core and accessory genomic variation, and they cannot both automatically identify, and subsequently expand, clusters of significantly similar isolates in large data sets spanning entire species. Here, we describe PopPUNK (ulation artitioning sing ucleotide -mers), a software implementing scalable and expandable annotation- and alignment-free methods for population analysis and clustering. Read More

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http://dx.doi.org/10.1101/gr.241455.118DOI Listing
February 2019

JACKS: joint analysis of CRISPR/Cas9 knockout screens.

Genome Res 2019 Jan 23. Epub 2019 Jan 23.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, United Kingdom.

Genome-wide CRISPR/Cas9 knockout screens are revolutionizing mammalian functional genomics. However, their range of applications remains limited by signal variability from different guide RNAs that target the same gene, which confounds gene effect estimation and dictates large experiment sizes. To address this problem, we report JACKS, a Bayesian method that jointly analyzes screens performed with the same guide RNA library. Read More

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http://dx.doi.org/10.1101/gr.238923.118DOI Listing
January 2019

Pou5f3, SoxB1, and Nanog remodel chromatin on high nucleosome affinity regions at zygotic genome activation.

Genome Res 2019 Jan 23. Epub 2019 Jan 23.

Department of Developmental Biology, Institute of Biology I, Faculty of Biology, Albert Ludwigs University of Freiburg, 79104, Freiburg, Germany.

The zebrafish embryo is transcriptionally mostly quiescent during the first 10 cell cycles, until the main wave of zygotic genome activation (ZGA) occurs, accompanied by fast chromatin remodeling. At ZGA, homologs of the mammalian stem cell transcription factors (TFs) Pou5f3, Nanog, and Sox19b bind to thousands of developmental enhancers to initiate transcription. So far, how these TFs influence chromatin dynamics at ZGA has remained unresolved. Read More

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http://dx.doi.org/10.1101/gr.240572.118DOI Listing
January 2019

A dynamic and integrated epigenetic program at distal regions orchestrates transcriptional responses to VEGFA.

Genome Res 2019 02 22;29(2):193-207. Epub 2019 Jan 22.

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Xin Hua Hospital, Shanghai Jiao Tong University, Shanghai 200240, China.

Cell behaviors are dictated by epigenetic and transcriptional programs. Little is known about how extracellular stimuli modulate these programs to reshape gene expression and control cell behavioral responses. Here, we interrogated the epigenetic and transcriptional response of endothelial cells to VEGFA treatment and found rapid chromatin changes that mediate broad transcriptomic alterations. Read More

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http://dx.doi.org/10.1101/gr.239053.118DOI Listing
February 2019
2 Reads

Guide Positioning Sequencing identifies aberrant DNA methylation patterns that alter cell identity and tumor-immune surveillance networks.

Genome Res 2019 02 22;29(2):270-280. Epub 2019 Jan 22.

Shanghai Public Health Clinical Center and Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute and Laboratory of RNA Epigenetics, Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 201508, China.

Aberrant DNA methylation is a distinguishing feature of cancer. Yet, how methylation affects immune surveillance and tumor metastasis remains ambiguous. We introduce a novel method, Guide Positioning Sequencing (GPS), for precisely detecting whole-genome DNA methylation with cytosine coverage as high as 96% and unbiased coverage of GC-rich and repetitive regions. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.240606.118
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http://dx.doi.org/10.1101/gr.240606.118DOI Listing
February 2019
4 Reads
14.630 Impact Factor

Large-scale discovery of mouse transgenic integration sites reveals frequent structural variation and insertional mutagenesis.

Genome Res 2019 Jan 18. Epub 2019 Jan 18.

The Jackson Laboratory, Bar Harbor, Maine 04609, USA.

Transgenesis has been a mainstay of mouse genetics for over 30 yr, providing numerous models of human disease and critical genetic tools in widespread use today. Generated through the random integration of DNA fragments into the host genome, transgenesis can lead to insertional mutagenesis if a coding gene or an essential element is disrupted, and there is evidence that larger scale structural variation can accompany the integration. The insertion sites of only a tiny fraction of the thousands of transgenic lines in existence have been discovered and reported, due in part to limitations in the discovery tools. Read More

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http://dx.doi.org/10.1101/gr.233866.117DOI Listing
January 2019
14.630 Impact Factor

Transcription factor activity and nucleosome organization in mitosis.

Genome Res 2019 02 17;29(2):250-260. Epub 2019 Jan 17.

Epigenetics of Stem Cells, Department of Developmental and Stem Cell Biology, Institut Pasteur, CNRS UMR3738, 75015 Paris, France.

Mitotic bookmarking transcription factors (BFs) maintain the capacity to bind to their targets during mitosis, despite major rearrangements of the chromatin. While they were thought to propagate gene regulatory information through mitosis by statically occupying their DNA targets, it has recently become clear that BFs are highly dynamic in mitotic cells. This represents both a technical and a conceptual challenge to study and understand the function of BFs: First, formaldehyde has been suggested to be unable to efficiently capture these transient interactions, leading to profound contradictions in the literature; and second, if BFs are not permanently bound to their targets during mitosis, it becomes unclear how they convey regulatory information to daughter cells. Read More

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http://dx.doi.org/10.1101/gr.243048.118DOI Listing
February 2019
1 Read
14.630 Impact Factor

CTCF sites display cell cycle-dependent dynamics in factor binding and nucleosome positioning.

Genome Res 2019 02 17;29(2):236-249. Epub 2019 Jan 17.

Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

CCCTC-binding factor (CTCF) plays a key role in the formation of topologically associating domains (TADs) and loops in interphase. During mitosis TADs are absent, but how TAD formation is dynamically controlled during the cell cycle is not known. Several contradicting observations have been made regarding CTCF binding to mitotic chromatin using both genomics- and microscopy-based techniques. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.241547.118
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http://dx.doi.org/10.1101/gr.241547.118DOI Listing
February 2019
8 Reads
14.630 Impact Factor

MicroRNAs reinforce repression of PRC2 transcriptional targets independently and through a feed-forward regulatory network.

Genome Res 2019 02 16;29(2):184-192. Epub 2019 Jan 16.

Center for Systems and Synthetic Biology, Institute for Cellular and Molecular Biology, Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas 78712, USA.

Gene expression can be regulated at multiple levels, but it is not known if and how there is broad coordination between regulation at the transcriptional and post-transcriptional levels. Transcription factors and chromatin regulate gene expression transcriptionally, whereas microRNAs (miRNAs) are small regulatory RNAs that function post-transcriptionally. Systematically identifying the post-transcriptional targets of miRNAs and the mechanism of transcriptional regulation of the same targets can shed light on regulatory networks connecting transcriptional and post-transcriptional control. Read More

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http://dx.doi.org/10.1101/gr.238311.118DOI Listing
February 2019

Gene duplication and genetic innovation in cereal genomes.

Genome Res 2019 02 16;29(2):261-269. Epub 2019 Jan 16.

Plant Genome Mapping Laboratory, University of Georgia, Athens, Georgia 30602, USA.

Organisms continuously require genetic variation to adapt to fluctuating environments, yet major evolutionary events are episodic, making the relationship between genome evolution and organismal adaptation of considerable interest. Here, by genome-wide comparison of sorghum, maize, and rice SNPs, we investigated reservoirs of genetic variations with high precision. For sorghum and rice, which have not experienced whole-genome duplication in 96 million years or more, tandem duplicates accumulate relatively more SNPs than paralogous genes retained from genome duplication. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.237511.118
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http://dx.doi.org/10.1101/gr.237511.118DOI Listing
February 2019
2 Reads

Transposon insertional mutagenesis in reveals -acting effects influencing species-dependent essential genes.

Genome Res 2019 Jan 11. Epub 2019 Jan 11.

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.

To understand how complex genetic networks perform and regulate diverse cellular processes, the function of each individual component must be defined. Comprehensive phenotypic studies of mutant alleles have been successful in model organisms in determining what processes depend on the normal function of a gene. These results are often ported to newly sequenced genomes by using sequence homology. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.232330.117
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http://dx.doi.org/10.1101/gr.232330.117DOI Listing
January 2019
1 Read

Systematic interrogation of human promoters.

Genome Res 2019 02 8;29(2):171-183. Epub 2019 Jan 8.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel.

Despite much research, our understanding of the architecture and -regulatory elements of human promoters is still lacking. Here, we devised a high-throughput assay to quantify the activity of approximately 15,000 fully designed sequences that we integrated and expressed from a fixed location within the human genome. We used this method to investigate thousands of native promoters and preinitiation complex (PIC) binding regions followed by in-depth characterization of the sequence motifs underlying promoter activity, including core promoter elements and TF binding sites. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.236075.118
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http://dx.doi.org/10.1101/gr.236075.118DOI Listing
February 2019
1 Read

Most chromatin interactions are not in linkage disequilibrium.

Genome Res 2019 Jan 7. Epub 2019 Jan 7.

Gladstone Institutes, San Francisco, California 94158, USA.

Chromatin interactions and linkage disequilibrium (LD) are both pairwise measurements between genomic loci that show block patterns along mammalian chromosomes. Their values are generally high for sites that are nearby in the linear genome but abruptly drop across block boundaries. One function of chromatin boundaries is to insulate regulatory domains from one another. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.238022.118
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http://dx.doi.org/10.1101/gr.238022.118DOI Listing
January 2019
3 Reads

PepQuery enables fast, accurate, and convenient proteomic validation of novel genomic alterations.

Genome Res 2019 Jan 4. Epub 2019 Jan 4.

Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Massively parallel or second-generation sequencing-based genomic studies continuously identify new genomic alterations that may lead to novel protein sequences, which are attractive candidates for disease biomarkers and therapeutic targets after proteomic validation. Integrative proteogenomic methods have been developed to use mass spectrometry (MS)-based proteomics data for such validation. These methods replace the reference sequence database in proteomic database searching with a customized protein database that incorporates sample- or disease-specific sequences derived from DNA or RNA sequencing, thus enabling the identification of novel protein sequences. Read More

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http://dx.doi.org/10.1101/gr.235028.118DOI Listing
January 2019

An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells.

Genome Res 2019 02 3;29(2):223-235. Epub 2019 Jan 3.

Genome Institute of Singapore, Singapore 138672.

The aberrant activities of transcription factors such as the androgen receptor (AR) underpin prostate cancer development. While the AR -regulation has been extensively studied in prostate cancer, information pertaining to the spatial architecture of the AR transcriptional circuitry remains limited. In this paper, we propose a novel framework to profile long-range chromatin interactions associated with AR and its collaborative transcription factor, erythroblast transformation-specific related gene (ERG), using chromatin interaction analysis by paired-end tag (ChIA-PET). Read More

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http://dx.doi.org/10.1101/gr.230243.117DOI Listing
February 2019
12 Reads

Ancient exapted transposable elements promote nuclear enrichment of human long noncoding RNAs.

Genome Res 2019 02 26;29(2):208-222. Epub 2018 Dec 26.

Department for BioMedical Research (DBMR), University of Bern, 3008 Bern, Switzerland.

The sequence domains underlying long noncoding RNA (lncRNA) activities, including their characteristic nuclear enrichment, remain largely unknown. It has been proposed that these domains can originate from neofunctionalized fragments of transposable elements (TEs), otherwise known as RIDLs (repeat insertion domains of lncRNA), although just a handful have been identified. It is challenging to distinguish functional RIDL instances against a numerous genomic background of neutrally evolving TEs. Read More

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http://dx.doi.org/10.1101/gr.229922.117DOI Listing
February 2019

Pathogenicity and selective constraint on variation near splice sites.

Genome Res 2019 02 26;29(2):159-170. Epub 2018 Dec 26.

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.

Mutations that perturb normal pre-mRNA splicing are significant contributors to human disease. We used exome sequencing data from 7833 probands with developmental disorders (DDs) and their unaffected parents, as well as more than 60,000 aggregated exomes from the Exome Aggregation Consortium, to investigate selection around the splice sites and quantify the contribution of splicing mutations to DDs. Patterns of purifying selection, a deficit of variants in highly constrained genes in healthy subjects, and excess de novo mutations in patients highlighted particular positions within and around the consensus splice site of greater functional relevance. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.238444.118
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http://dx.doi.org/10.1101/gr.238444.118DOI Listing
February 2019
12 Reads

Identification of regulatory elements from nascent transcription using dREG.

Genome Res 2019 02 20;29(2):293-303. Epub 2018 Dec 20.

Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853, USA.

Our genomes encode a wealth of transcription initiation regions (TIRs) that can be identified by their distinctive patterns of actively elongating RNA polymerase. We previously introduced dREG to identify TIRs using PRO-seq data. Here, we introduce an efficient new implementation of dREG that uses PRO-seq data to identify both uni- and bidirectionally transcribed TIRs with 70% improvement in accuracy, three- to fourfold higher resolution, and >100-fold increases in computational efficiency. Read More

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http://dx.doi.org/10.1101/gr.238279.118DOI Listing
February 2019

Anchor: trans-cell type prediction of transcription factor binding sites.

Genome Res 2019 02 19;29(2):281-292. Epub 2018 Dec 19.

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, USA.

The ENCyclopedia of DNA Elements (ENCODE) consortium has generated transcription factor (TF) binding ChIP-seq data covering hundreds of TF proteins and cell types; however, due to limits on time and resources, only a small fraction of all possible TF-cell type pairs have been profiled. One solution is to build machine learning models trained on currently available epigenomic data sets that can be applied to the remaining missing pairs. A major challenge is that TF binding sites are cell-type-specific, which can be attributed to cellular contexts such as chromatin accessibility. Read More

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http://dx.doi.org/10.1101/gr.237156.118DOI Listing
February 2019
1 Read

Global analysis of protein homomerization in .

Genome Res 2019 01 19;29(1):135-145. Epub 2018 Dec 19.

Department of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.

In vivo analyses of the occurrence, subcellular localization, and dynamics of protein-protein interactions (PPIs) are important issues in functional proteomic studies. The bimolecular fluorescence complementation (BiFC) assay has many advantages in that it provides a reliable way to detect PPIs in living cells with minimal perturbation of the structure and function of the target proteins. Previously, to facilitate the application of the BiFC assay to genome-wide analysis of PPIs, we generated a collection of yeast strains expressing full-length proteins tagged with the N-terminal fragment of Venus (VN), a yellow fluorescent protein variant, from their own native promoters. Read More

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http://dx.doi.org/10.1101/gr.231860.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314163PMC
January 2019

Human papillomavirus and the landscape of secondary genetic alterations in oral cancers.

Genome Res 2019 01 18;29(1):1-17. Epub 2018 Dec 18.

Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.241141.118
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http://dx.doi.org/10.1101/gr.241141.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314162PMC
January 2019
26 Reads
14.630 Impact Factor

A quantitative framework for characterizing the evolutionary history of mammalian gene expression.

Genome Res 2019 01 14;29(1):53-63. Epub 2018 Dec 14.

Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

The evolutionary history of a gene helps predict its function and relationship to phenotypic traits. Although sequence conservation is commonly used to decipher gene function and assess medical relevance, methods for functional inference from comparative expression data are lacking. Here, we use RNA-seq across seven tissues from 17 mammalian species to show that expression evolution across mammals is accurately modeled by the Ornstein-Uhlenbeck process, a commonly proposed model of continuous trait evolution. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.237636.118
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http://dx.doi.org/10.1101/gr.237636.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314168PMC
January 2019
2 Reads

Nucleosome remodeling at origins of global genome-nucleotide excision repair occurs at the boundaries of higher-order chromatin structure.

Genome Res 2019 01 14;29(1):74-84. Epub 2018 Dec 14.

Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.

Repair of UV-induced DNA damage requires chromatin remodeling. How repair is initiated in chromatin remains largely unknown. We recently demonstrated that global genome-nucleotide excision repair (GG-NER) in chromatin is organized into domains in relation to open reading frames. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.237198.118
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http://dx.doi.org/10.1101/gr.237198.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314166PMC
January 2019
1 Read

Hormone-control regions mediate steroid receptor-dependent genome organization.

Genome Res 2019 01 14;29(1):29-39. Epub 2018 Dec 14.

Gene Regulation, Stem Cells and Cancer Program, Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.

In breast cancer cells, some topologically associating domains (TADs) behave as hormonal gene regulation units, within which gene transcription is coordinately regulated in response to steroid hormones. Here we further describe that responsive TADs contain 20- to 100-kb-long clusters of intermingled estrogen receptor (ESR1) and progesterone receptor (PGR) binding sites, hereafter called hormone-control regions (HCRs). In T47D cells, we identified more than 200 HCRs, which are frequently bound by unliganded ESR1 and PGR. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.243824.118
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http://dx.doi.org/10.1101/gr.243824.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314164PMC
January 2019
1 Read

Transposable element insertions in fission yeast drive adaptation to environmental stress.

Genome Res 2019 01 12;29(1):85-95. Epub 2018 Dec 12.

Section on Eukaryotic Transposable Elements, Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.

Cells are regularly exposed to a range of naturally occurring stress that can restrict growth or cause lethality. In response, cells activate expression networks with hundreds of genes that together increase resistance to common environmental insults. However, stress response networks can be insufficient to ensure survival, which raises the question of whether cells possess genetic programs that can promote adaptation to novel forms of stress. Read More

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http://dx.doi.org/10.1101/gr.239699.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314160PMC
January 2019

Rapid reversible changes in compartments and local chromatin organization revealed by hyperosmotic shock.

Genome Res 2019 01 6;29(1):18-28. Epub 2018 Dec 6.

Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, E-08003 Barcelona, Spain.

Nuclear architecture is decisive for the assembly of transcriptional responses. However, how chromosome organization is dynamically modulated to permit rapid and transient transcriptional changes in response to environmental challenges remains unclear. Here we show that hyperosmotic stress disrupts different levels of chromosome organization, ranging from A/B compartment changes to reduction in the number and insulation of topologically associating domains (TADs). Read More

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http://dx.doi.org/10.1101/gr.238527.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314167PMC
January 2019
2 Reads

Minerva: an alignment- and reference-free approach to deconvolve Linked-Reads for metagenomics.

Genome Res 2019 01 6;29(1):116-124. Epub 2018 Dec 6.

Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine of Cornell University, New York, New York 10065, USA.

Emerging Linked-Read technologies (aka read cloud or barcoded short-reads) have revived interest in short-read technology as a viable approach to understand large-scale structures in genomes and metagenomes. Linked-Read technologies, such as the 10x Chromium system, use a microfluidic system and a specialized set of 3' barcodes (aka UIDs) to tag short DNA reads sourced from the same long fragment of DNA; subsequently, the tagged reads are sequenced on standard short-read platforms. This approach results in interesting compromises. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.235499.118
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http://dx.doi.org/10.1101/gr.235499.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314158PMC
January 2019
9 Reads

Epigenetic mapping of the metabolome reveals mediators of the epigenotype-phenotype map.

Genome Res 2019 01 30;29(1):96-106. Epub 2018 Nov 30.

Laboratory of Genetics, Wageningen University and Research, 6708 PB Wageningen, The Netherlands.

Identifying the sources of natural variation underlying metabolic differences between plants will enable a better understanding of plant metabolism and provide insights into the regulatory networks that govern plant growth and morphology. So far, however, the contribution of epigenetic variation to metabolic diversity has been largely ignored. In the present study, we utilized a panel of epigenetic recombinant inbred lines (epiRILs) to assess the impact of epigenetic variation on the metabolic composition. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.232371.117
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http://dx.doi.org/10.1101/gr.232371.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314165PMC
January 2019
1 Read

Comparison and assessment of family- and population-based genotype imputation methods in large pedigrees.

Genome Res 2019 01 4;29(1):125-134. Epub 2018 Dec 4.

Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar.

Genotype imputation is widely used in genome-wide association studies to boost variant density, allowing increased power in association testing. Many studies currently include pedigree data due to increasing interest in rare variants coupled with the availability of appropriate analysis tools. The performance of population-based (subjects are unrelated) imputation methods is well established. Read More

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http://dx.doi.org/10.1101/gr.236315.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314157PMC
January 2019
1 Read

Accelerated rates of large-scale mutations in the presence of copper and nickel.

Genome Res 2019 01 28;29(1):64-73. Epub 2018 Nov 28.

Department of Biology, McGill University, Montréal, Québec H3A 1B1, Canada.

Mutation rate variation has been under intense investigation for decades. Despite these efforts, little is known about the extent to which environmental stressors accelerate mutation rates and influence the genetic load of populations. Moreover, most studies on stressors have focused on unicellular organisms and point mutations rather than large-scale deletions and duplications (copy number variations [CNVs]). Read More

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http://dx.doi.org/10.1101/gr.234724.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314161PMC
January 2019

Damage-responsive elements in regeneration.

Genome Res 2018 12 20;28(12):1852-1866. Epub 2018 Nov 20.

Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona 08028, Catalonia, Spain.

One of the most important questions in regenerative biology is to unveil how and when genes change expression and trigger regeneration programs. The resetting of gene expression patterns during response to injury is governed by coordinated actions of genomic regions that control the activity of multiple sequence-specific DNA binding proteins. Using genome-wide approaches to interrogate chromatin function, we here identify the elements that regulate tissue recovery in imaginal discs, which show a high regenerative capacity after genetically induced cell death. Read More

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http://dx.doi.org/10.1101/gr.233098.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280756PMC
December 2018
12 Reads

Quantification of somatic mutation flow across individual cell division events by lineage sequencing.

Genome Res 2018 12 20;28(12):1901-1918. Epub 2018 Nov 20.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

Mutation data reveal the dynamic equilibrium between DNA damage and repair processes in cells and are indispensable to the understanding of age-related diseases, tumor evolution, and the acquisition of drug resistance. However, available genome-wide methods have a limited ability to resolve rare somatic variants and the relationships between these variants. Here, we present lineage sequencing, a new genome sequencing approach that enables somatic event reconstruction by providing quality somatic mutation call sets with resolution as high as the single-cell level in subject lineages. Read More

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http://dx.doi.org/10.1101/gr.238543.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280753PMC
December 2018
14 Reads

Widespread roles of enhancer-like transposable elements in cell identity and long-range genomic interactions.

Genome Res 2019 01 19;29(1):40-52. Epub 2018 Nov 19.

CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

A few families of transposable elements (TEs) have been shown to evolve into -regulatory elements (CREs). Here, to extend these studies to all classes of TEs in the human genome, we identified widespread enhancer-like repeats (ELRs) and find that ELRs reliably mark cell identities, are enriched for lineage-specific master transcription factor binding sites, and are mostly primate-specific. In particular, elements of MIR and L2 TE families whose abundance co-evolved across chordate genomes, are found as ELRs in most human cell types examined. Read More

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http://dx.doi.org/10.1101/gr.235747.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314169PMC
January 2019

Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of transcripts under balancing selection.

Genome Res 2018 12 16;28(12):1812-1825. Epub 2018 Nov 16.

Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Read More

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http://genome.cshlp.org/lookup/doi/10.1101/gr.240390.118
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http://dx.doi.org/10.1101/gr.240390.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280757PMC
December 2018
21 Reads