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Genome Research

Beibei Xin, Remo Rohs
The very small fraction of putative binding sites (BSs) that are occupied by transcription factors (TFs) in vivo can be highly variable across different cell types. This observation has been partly attributed to changes in chromatin accessibility and histone modification (HM) patterns surrounding BSs. Previous studies focusing on BSs within DNA regulatory regions found correlations between HM patterns and TF binding specificities. However, a mechanistic understanding of TF-DNA binding specificity determinants is still not available...
January 11, 2018: Genome Research
Hyongbum Henry Kim, Wonjoo Kim, Sangeun Lee, Han Sang Kim, Minjung Song, Yong Hoon Cha, Young-Hoon Kim, Jeonghong Shin, Eun-Seo Lee, Yeonsoo Joo, Jae J Song, Eun Ju Choi, Jae W Choi, Jinu Lee, Moonkyung Kang, Jong In Yook, Min Goo Lee, Yeon-Soo Kim, Soonmyung Paik
KRAS is the most frequently mutated oncogene in human tumors and its activating mutations represents important therapeutic targets. The combination of Cas9 and guide RNA from the CRISPR-Cas system recognizes a specific DNA sequence and makes a double-strand break, which enables editing of the relevant genes. Here we harnessed CRISPR to specifically target mutant KRAS alleles in cancer cells. We screened guide RNAs using a reporter system and validated them in cancer cells after lentiviral delivery of Cas9 and guide RNA...
January 11, 2018: Genome Research
Jun Ding, Bruce Aronow, Naftali Kaminski, Joseph Kitzmiller, Jeffrey Whitsett, Ziv Bar-Joseph
Generating detailed and accurate organogenesis models using single cell RNA-seq data remains a major challenge. Current methods have relied primarily on the assumption that decedent cells are similar to their parents in terms of gene expression levels. These assumptions do not always hold for in-vivo studies which often include infrequently sampled, un-synchronized and diverse cell populations. Thus, additional information may be needed to determine the correct ordering and branching of progenitor cells and the set of transcription factors (TFs) that are active during advancing stages of organogenesis...
January 9, 2018: Genome Research
Hemangi G Chaudhari, Barak A Cohen
In the genome, most occurrences of transcription factor binding sites (TFBS) have no cis-regulatory activity, which suggests that flanking sequences contain information that distinguishes functional from non-functional TFBS. We interrogated the role of flanking sequences near Activator Protein 1 (AP-1) binding sites that reside in DNase I Hypersensitive Sites (DHS) and regions annotated as Enhancers. In these regions we found that sequence features directly adjacent to the core motif distinguish high from low activity AP-1 sites...
January 5, 2018: Genome Research
Kazuhiro Nakajima, Yue Zhou, Akiko Tomita, Yoshihiro Hirade, Channabasavaiah B Gurumurthy, Shinichiro Nakada
CRISPR/Cas9, which generates DNA double-strand breaks (DSBs) at target loci, is a powerful tool for editing genomes when codelivered with a donor DNA template. However, DSBs, which are the most deleterious type of DNA damage, often result in unintended nucleotide insertions/deletions (indels) via mutagenic nonhomologous end joining. We developed a strategy for precise gene editing that does not generate DSBs. We show that a combination of single nicks in the target gene and donor plasmid (SNGD) using Cas9D10A nickase promotes efficient nucleotide substitution by gene editing...
December 22, 2017: Genome Research
John R Tyson, Nigel J O'Neil, Miten Jain, Hugh E Olsen, Philip Hieter, Terrance P Snutch
Advances in long read single molecule sequencing have opened new possibilities for 'benchtop' whole genome sequencing. The Oxford Nanopore Technologies MinION is a portable device that uses nanopore technology that can directly sequence DNA molecules. MinION single molecule long sequence reads are well suited for de novo assembly of complex genomes as they facilitate the construction of highly contiguous physical genome maps obviating the need for labor-intensive physical genome mapping. Long sequence reads can also be used to delineate complex chromosomal rearrangements, such as those that occur in tumour cells, that can confound analysis using short reads...
December 22, 2017: Genome Research
Hui Fan, Pin Lv, Xiangru Huo, Jicheng Wu, Qianfeng Wang, Lu Cheng, Yun Liu, Qiqun Tang, Ling Zhang, Feng Zhang, Xiaoqi Zheng, Hao Wu, Bo Wen
The eukaryotic chromosomes are folded into higher-order conformation to coordinate genome functions. Besides long-range chromatin loops, recent chromosome conformation capture (3C)-based studies indicated the higher level of chromatin structures including compartments and topologically associating domains (TADs), which may serve as units of genome organization and functions. However, the molecular machinery underlying these hierarchically three-dimensional (3D) chromatin architectures remains poorly understood...
December 22, 2017: Genome Research
Hector L Franco, Anusha Nagari, Venkat S Malladi, Wenqian Li, Yuanxin Xi, Dana Richardson, Kendra L Allton, Kaori Tanaka, Jing Li, Shino Murakami, Khandan Keyomarsi, Mark T Bedford, Xiaobing Shi, Wei Li, Michelle C Barton, Sharon Y R Dent, W Lee Kraus
Noncoding transcription is a defining feature of active enhancers, linking transcription factor (TF) binding to the molecular mechanisms controlling gene expression. To determine the relationship between enhancer activity and biological outcomes in breast cancers, we profiled the transcriptomes (using GRO-seq and RNA-seq) and epigenomes (using ChIP-seq) of 11 different human breast cancer cell lines representing five major molecular subtypes of breast cancer, as well as two immortalized ("normal") human breast cell lines...
December 22, 2017: Genome Research
Jianghan Qu, Emily Hodges, Antoine Molaro, Pascal Gagneux, Matthew D Dean, Gregory J Hannon, Andrew D Smith
DNA methylation in the germline is among the most important factors influencing the evolution of mammalian genomes. Yet little is known about its evolutionary rate or the fraction of the methylome that has undergone change. We compared whole-genome, single-CpG DNA methylation profiles in sperm of seven species: human, chimpanzee, gorilla, rhesus macaque, mouse, rat and dog, to investigate epigenomic evolution. We developed a phylo-epigenetic model for DNA methylation that accommodates the correlation of states at neighboring sites and allows for inference of ancestral states...
December 19, 2017: Genome Research
Pieter Spealman, Armaghan Naik, Gemma May, Scott Kuersten, Lindsay Freebert, Robert Murphy, Joel McManus
Upstream open reading frames (uORFs), located in transcript leaders (5' UTRs), are potent cis-acting regulators of translation and mRNA turnover. Recent genome-wide ribosome profiling studies suggest that thousands of uORFs initiate with non-AUG start codons. While intriguing, these non-AUG uORF predictions have been made without statistical control or validation, thus the importance of these elements remains to be demonstrated. To address this, we took a comparative genomics approach to study AUG and non-AUG uORFs...
December 18, 2017: Genome Research
Vahid Aslanzadeh, Yuanhua Huang, Guido Sanguinetti, Jean D Beggs
The functional consequences for alternative splicing of altering the transcription rate have been the subject of intensive study in mammalian cells but less is known about effects on splicing of changing the transcription rate in yeast. We present several lines of evidence showing that slow RNA polymerase II elongation increases both co-transcriptional splicing and splicing efficiency and faster elongation reduces co-transcriptional splicing and splicing efficiency in budding yeast, suggesting that splicing is more efficient when co-transcriptional...
December 18, 2017: Genome Research
Jake Yeung, Jérôme Mermet, Céline Jouffe, Julien Marquis, Aline Charpagne, Frédéric Gachon, Felix Naef
Temporal control of physiology requires the interplay between gene networks involved in daily timekeeping and tissue function across different organs. How the circadian clock interweaves with tissue-specific transcriptional programs is poorly understood. Here we dissected temporal and tissue-specific regulation at multiple gene regulatory layers by examining mouse tissues with an intact or disrupted clock over time. Integrated analysis uncovered two distinct regulatory modes underlying tissue-specific rhythms: tissue-specific oscillations in transcription factor (TF) activity, which were linked to feeding-fasting cycles in liver and sodium homeostasis in kidney; and co-localized binding of clock and tissue-specific transcription factors at distal enhancers...
December 18, 2017: Genome Research
Shengdong Ke, Vincent Anquetil, Jorge Rojas Zamalloa, Alisha Maity, Anthony Yang, Mauricio A Arias, Sergey Kalachikov, James J Russo, Jingyue Ju, Lawrence A Chasin
To illuminate the extent and roles of exonic sequences in the splicing of human RNA transcripts, we conducted saturation mutagenesis of a 51-nt internal exon in a three-exon minigene. All possible single and tandem dinucleotide substitutions were surveyed. Using high-throughput genetics, 5560 minigene molecules were assayed for splicing in human HEK293 cells. Up to 70% of mutations produced substantial (greater than twofold) phenotypes of either increased or decreased splicing. Of all predicted secondary structural elements, only a single 15-nt stem-loop showed a strong correlation with splicing, acting negatively...
December 14, 2017: Genome Research
Konstantin Popadin, Stephan Peischl, Marco Garieri, M Reza Sailani, Audrey Letourneau, Federico Santoni, Samuel W Lukowski, Georgii A Bazykin, Sergey Nikolaev, Diogo Meyer, Laurent Excoffier, Alexandre Reymond, Stylianos E Antonarakis
The majority of aneuploid fetuses are spontaneously miscarried. Nevertheless, some aneuploid individuals survive despite the strong genetic insult. Here, we investigate if the survival probability of aneuploid fetuses is affected by the genome-wide burden of slightly deleterious variants. We analyzed two cohorts of live-born Down syndrome individuals (388 genotyped samples and 16 fibroblast transcriptomes) and observed a deficit of slightly deleterious variants on Chromosome 21 and decreased transcriptome-wide variation in the expression level of highly constrained genes...
December 13, 2017: Genome Research
Eric J Belfield, Zhong Jie Ding, Fiona J C Jamieson, Anne M Visscher, Shao Jian Zheng, Aziz Mithani, Nicholas P Harberd
Mutation is the source of genetic variation and fuels biological evolution. Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism. Here, we determine the genome-wide effects of MMR on mutation. We first identify almost 9000 mutations accumulated over five generations in eight MMR-deficient mutation accumulation (MA) lines of the model plant species, Arabidopsis thaliana We then show that MMR deficiency greatly increases the frequency of both smaller-scale insertions and deletions (indels) and of single-nucleotide variant (SNV) mutations...
December 12, 2017: Genome Research
Lishi Li, Yulong Song, Xinrui Shi, Jianheng Liu, Shaolei Xiong, Wanying Chen, Qiang Fu, Zichao Huang, Nannan Gu, Rui Zhang
Adenosine-to-inosine (A-to-I) RNA editing regulates miRNA biogenesis and function. To date, fewer than 160 miRNA editing sites have been identified. Here, we present a quantitative atlas of miRNA A-to-I editing through the profiling of 201 pri-miRNA samples and 4694 mature miRNA samples in human, mouse, and Drosophila. We identified 4162 sites present in ∼80% of the pri-miRNAs and 574 sites in mature miRNAs. miRNA editing is prevalent in many tissue types in human. However, high-level editing is mostly found in neuronal tissues in mouse and Drosophila Interestingly, the edited miRNAs in neuronal and non-neuronal tissues in human gain two distinct sets of new targets, which are significantly associated with cognitive and organ developmental functions, respectively...
December 12, 2017: Genome Research
Jaaved Mohammed, Alex S Flynt, Alexandra M Panzarino, Md Mosharrof Hussein Mondal, Matthew DeCruz, Adam Siepel, Eric C Lai
To assess miRNA evolution across the Drosophila genus, we analyzed several billion small RNA reads across 12 fruit fly species. These data permit comprehensive curation of species- and clade-specific variation in miRNA identity, abundance, and processing. Among well-conserved miRNAs, we observed unexpected cases of clade-specific variation in 5' end precision, occasional antisense loci, and putatively noncanonical loci. We also used strict criteria to identify a large set (649) of novel, evolutionarily restricted miRNAs...
December 12, 2017: Genome Research
Jesper Grud Skat Madsen, Alexander Rauch, Elvira Laila Van Hauwaert, Søren Fisker Schmidt, Marc Winnefeld, Susanne Mandrup
The ability to predict transcription factors based on sequence information in regulatory elements is a key step in systems-level investigation of transcriptional regulation. Here, we have developed a novel tool, IMAGE, for precise prediction of causal transcription factors based on transcriptome profiling and genome-wide maps of enhancer activity. High precision is obtained by combining a near-complete database of position weight matrices (PWMs), generated by compiling public databases and systematic prediction of PWMs for uncharacterized transcription factors, with a state-of-the-art method for PWM scoring and a novel machine learning strategy, based on both enhancers and promoters, to predict the contribution of motifs to transcriptional activity...
December 12, 2017: Genome Research
Craig B Lowe, Nicelio Sanchez-Luege, Timothy R Howes, Shannon D Brady, Rhea R Richardson, Felicity C Jones, Michael A Bell, David M Kingsley
We present a method to detect copy number variants (CNVs) that are differentially present between two groups of sequenced samples. We use a finite-state transducer where the emitted read depth is conditioned on the mappability and GC-content of all reads that occur at a given base position. In this model, the read depth within a region is a mixture of binomials, which in simulations matches the read depth more closely than the often-used negative binomial distribution. The method analyzes all samples simultaneously, preserving uncertainty as to the breakpoints and magnitude of CNVs present in an individual when it identifies CNVs differentially present between the two groups...
December 11, 2017: Genome Research
Carol C L Chen, Preeti Goyal, Mohammad M Karimi, Marie H Abildgaard, Hiroshi Kimura, Matthew C Lorincz
Phosphorylation of histone H3 at serine 10 (H3S10ph) by Aurora kinases plays an important role in mitosis; however, H3S10ph also marks regulatory regions of inducible genes in interphase mammalian cells, implicating mitosis-independent functions. Using the fluorescent ubiquitin-mediated cell cycle indicator (FUCCI), we found that 30% of the genome in interphase mouse embryonic stem cells (ESCs) is marked with H3S10ph. H3S10ph broadly demarcates gene-rich regions in G1 and is positively correlated with domains of early DNA replication timing (RT) but negatively correlated with H3K9me2 and lamin-associated domains (LADs)...
December 11, 2017: Genome Research
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