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Genome Research

Le Li, Yuwei Gao, Qiong Wu, Alfred Cheng, Kevin Yip
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...
February 19, 2019: Genome Research
Mia Jaffe, Adam Dziulko, Justin D Smith, Robert P St Onge, Sasha F Levy, Gavin Sherlock
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. Here, we developed a pooled-growth CRISPRi-based sequencing assay for genetic interactions, CRISPRiSeq, that increases throughput such that GIs can be easily assayed across multiple growth conditions...
February 19, 2019: Genome Research
Meng Wang, Bernardo Lemos
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, Drosophila , and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity...
February 14, 2019: Genome Research
Michal Pawlak, Katarzyna Z Kedzierska, Maciej Migdal, Karim Abu Nahia, Jordan A Ramilowski, Lukasz Bugajski, Kosuke Hashimoto, Aleksandra Marconi, Katarzyna Piwocka, Piero Carninci, Cecilia L Winata
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...
February 13, 2019: Genome Research
Marta Farré, Jaebum Kim, Anastasia A Proskuryakova, Yang Zhang, Anastasia I Kulemzina, Qiye Li, Yang Zhou, Yingqi Xiong, Jennifer L Johnson, Polina Perelman, Warren E Johnson, Wesley C Warren, Anna V Kukekova, Guojie Zhang, Stephen J O'Brien, Oliver A Ryder, Alexander S Graphodatsky, Jian Ma, Harris A Lewin, Denis M Larkin
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. We found that the lineage leading to the ruminant ancestor after the split from other cetartiodactyls, was characterized by mostly intrachromosomal changes while the lineage leading to the pecoran ancestor (including all livestock ruminants) included multiple interchromosomal changes...
February 13, 2019: Genome Research
Bo Zhou, Steve S Ho, Stephanie U Greer, Xiaowei Zhu, John M Bell, Joseph G Arthur, Noah Spies, Xianglong Zhang, Seunggyu Byeon, Reenal Pattni, Noa Ben-Efraim, Michael S Haney, Rajini R Haraksingh, Giltae Song, Hanlee P Ji, Dimitri Perrin, Wing H Wong, Alexej Abyzov, Alexander E Urban
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. Such information is essential for the correct interpretation and understanding of the vast troves of existing functional genomics and epigenomics data for K562. We performed and integrated deep-coverage whole-genome (short-insert), mate-pair, and linked-read sequencing as well as karyotyping and array CGH analysis to identify a wide spectrum of genome characteristics in K562: copy numbers (CN) of aneuploid chromosome segments at high-resolution, SNVs and indels (both corrected for CN in aneuploid regions), loss of heterozygosity, megabase-scale phased haplotypes often spanning entire chromosome arms, structural variants (SVs), including small and large-scale complex SVs and nonreference retrotransposon insertions...
February 8, 2019: Genome Research
Dana Sherill-Rofe, Dolev Rahat, Steven Findlay, Anna Mellul, Irene Guberman, Maya Braun, Idit Bloch, Alon Lalezri, Arash Samiei, Ruslan Sadreyev, Michal Goldberg, Alexandre Orthwein, Aviad Zick, Yuval Tabach
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, genomic rearrangements and are associated with numerous genetic disorders and cancer. Despite intensive research, the HRR pathway is not yet fully mapped. Phylogenetic profiling analysis, which detects functional linkage between genes using co-evolution, is a powerful approach to identify factors in many pathways. Nevertheless, phylogenetic profiling has limited predictive power when analyzing pathways with complex evolutionary dynamics such as the HRR...
February 4, 2019: Genome Research
Dominik Hartl, Arnaud R Krebs, Ralph S Grand, Tuncay Baubec, Luke Isbel, Christiane Wirbelauer, Lukas Burger, Dirk Schubeler
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. This revealed that CpG density significantly improves motif-based prediction of transcription factor binding...
February 1, 2019: Genome Research
Keerthi T Chathoth, Nicolae Radu Zabet
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...
February 1, 2019: Genome Research
Emily R Miraldi, Maria Pokrovskii, Aaron Waters, Dayanne M Castro, Nick De Veaux, Jason Hall, June-Yong Lee, Maria Ciofani, Aviv Madar, Nick Carriero, Dan Littman, Richard Bonneau
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 transcription-factor 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 influence gene expression modeling. We rigorously test our methods in the context of T Helper Cell Type 17 (Th17) differentiation, generating new ATAC-seq data to complement existing Th17 genomic resources (gene expression data, TF knock-outs and ChIP-seq experiments)...
January 29, 2019: Genome Research
Marcel Smid, Saskia Wilting, Katharina Uhr, Germán Rodriguez-Gonzalez, Vanja de Weerd, Wendy Prager-Van der Smissen, Michelle van der Vlugt-Daane, Anne van Galen, Serena Nik-Zainal, Adam Butler, Sancha Martin, Helen Davies, Johan Staaf, Marc van de Vijver, Andrea Richardson, Gaeten MacGrogan, Roberto Salgado, Gert van den Eynden, Colin Purdie, Alastair Thompson, Carlos Caldas, Paul Span, Fred Sweep, Peter Simpson, Sunil Lakhani, Steven van Laere, Christine Desmedt, Angelo Paradiso, Jorunn Eyfjord, Annegien Broeks, Anne Vincent-Solomon, Andrew Futreal, Stian Knappskog, Tara King, Alain Viari, Anne-Lise Børresen-Dale, Hendrik Stunnenberg, Mike Stratton, John Foekens, Anieta Sieuwerts, John Martens
Circular RNAs (circRNAs) are a class of RNA 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. Of the circRNAs that match exon-boundaries of the same gene, 668 showed a poor or even negative (R<0.2) correlation with the expression level of the linear gene...
January 28, 2019: Genome Research
Brittany L Daughtry, Jimi L Rosenkrantz, Nathan H Lazar, Suzanne S Fei, Nash Redmayne, Kristof A Torkenczy, Andrew Adey, Melissa Yan, Lina Gao, Byung Park, Kimberly A Nevonen, Lucia Carbone, Shawn L Chavez
Aneuploidy that arises during meiosis and/or mitosis is a major contributor to early embryo loss. We previously demonstrated that human preimplantation embryos encapsulate mis-segregated 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 non-human 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 (N=50) of disassembled rhesus cleavage-stage embryos...
January 25, 2019: Genome Research
Kaia Mattioli, Pieter-Jan Volders, Chiara Gerhardinger, James C Lee, Philipp G Maass, Marta Melé, John L Rinn
Transcription initiates at both coding and non-coding genomic elements, including mRNA and long non-coding RNA (lncRNA) core promoters and enhancer RNAs (eRNAs). However, each class has different expression profiles 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. Here, we address this question using computational approaches and massively parallel reporter assays (MPRA) surveying hundreds of promoters and enhancers...
January 25, 2019: Genome Research
Josefina Ocampo, Razvan V Chereji, Peter R Eriksson, David J Clark
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 non-redundant, supporting a model in which the +1 nucleosome is positioned by RSC and then used as a reference nucleosome by the spacing enzymes...
January 25, 2019: Genome Research
Jeramiah J Smith, Nataliya Timoshevskaya, Vladimir A Timoshevskiy, Melissa C Keinath, Drew Hardy, S Randal Voss
The axolotl ( Ambystoma mexicanum ) 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. We adapted an established mapping approach to leverage dense SNP typing information and for the first time assemble the axolotl genome into 14 chromosomes...
January 24, 2019: Genome Research
John A Lees, Simon R Harris, Gerry Tonkin-Hill, Rebecca A Gladstone, Stephanie W Lo, Jeffrey N Weiser, Jukka Corander, Stephen D Bentley, Nicholas J Croucher
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 (<u>Pop</u>ulation <u>P</u>artitioning <u>U</u>sing <u>N</u>ucleotide <u>K</u> -mers), a software implementing scalable and expandable annotation- and alignment-free methods for population analysis and clustering...
January 24, 2019: Genome Research
Felicity Allen, Anton Khodak, Fiona Behan, Francesco Iorio, Kosuke Yusa, Mathew Garnett, Leopold Parts
CRISPR/Cas9 knockout screens are revolutionizing mammalian functional genomics. Their range of applications remains limited by signal variability from different guideRNAs 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. Modeling the variable guide efficacies greatly improves hit identification over processing a single screen at a time, and outperforms existing methods...
January 23, 2019: Genome Research
Marina Veil, Lev Yampolsky, Bjoern Gruening, Daria Onichtchouk
The zebrafish embryo is mostly transcriptionally 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 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. To address this question, we analyzed nucleosome positions in wild-type and Maternal-Zygotic (MZ) mutants for pou5f3 and nanog by MNase-seq...
January 23, 2019: Genome Research
Shiyan Wang, Jiahuan Chen, Sara P Garcia, Xiaodong Liang, Fang Zhang, Pengyi Yan, Huijing Yu, Weiting Wei, Zixuan Li, Jingfang Wang, Huangying Le, Zeguang Han, Xusheng Luo, Daniel S Day, Sean M Stevens, Yan Zhang, Peter J Park, Zhi-Jie Liu, Kun Sun, Guo-Cheng Yuan, William T Pu, Bing Zhang
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. VEGFA-responsive genes were associated with active promoters, but changes in promoter histone marks were not tightly linked to gene expression changes...
January 22, 2019: Genome Research
Jin Li, Yan Li, Wei Li, Huaibing Luo, Yanping Xi, Shihua Dong, Ming Gao, Peng Xu, Baolong Zhang, Ying Liang, Qingping Zou, Xin Hu, Lina Peng, Dan Zou, Ting Wang, Hongbo Yang, Cizhong Jiang, Shaoliang Peng, Feizhen Wu, Wenqiang Yu
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. Systematic comparisons of GPS with whole-genome bisulfite sequencing (WGBS) found that methylation difference between gene body and promoter is an effective predictor of gene expression with a correlation coefficient of 0...
January 22, 2019: Genome Research
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