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Oana Ursu, Nathan Boley, Maryna Taranova, Y X Rachel Wang, Galip Gurkan Yardimci, William Stafford Noble, Anshul Kundaje
Motivation: The three-dimensional organization of chromatin plays a critical role in gene regulation and disease. High-throughput chromosome conformation capture experiments such as Hi-C are used to obtain genome-wide maps of 3D chromatin contacts. However, robust estimation of data quality and systematic comparison of these contact maps is challenging due to the multi-scale, hierarchical structure of chromatin contacts and the resulting properties of experimental noise in the data. Measuring concordance of contact maps is important for assessing reproducibility of replicate experiments and for modeling variation between different cellular contexts...
March 15, 2018: Bioinformatics
Jinlei Han, Zhiliang Zhang, Kai Wang
It is well known that the chromosomes are organized in the nucleus and this spatial arrangement of genome play a crucial role in gene regulation and genome stability. Different techniques have been developed and applied to uncover the intrinsic mechanism of genome architecture, especially the chromosome conformation capture (3C) and 3C-derived methods. 3C and 3C-derived techniques provide us approaches to perform high-throughput chromatin architecture assays at the genome scale. However, the advantage and disadvantage of current methodologies of C-technologies have not been discussed extensively...
2018: Molecular Cytogenetics
Matteo Vecellio, Adrian Cortes, Amity R Roberts, Jonathan Ellis, Carla Jayne Cohen, Julian C Knight, Matthew A Brown, Paul Bowness, Bryan Paul Wordsworth
Objectives: To explore the functions of RUNX3 single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS). Methods: Individual SNP associations were evaluated in 4230 UK cases. Their effects on transcription factor (TF) binding, transcription regulation, chromatin modifications, gene expression and gene interactions were tested by database interrogation, luciferase reporter assays, electrophoretic mobility gel shifts, chromatin immunoprecipitation and real-time PCR...
2018: RMD Open
Joseph S Baxter, Olivia C Leavy, Nicola H Dryden, Sarah Maguire, Nichola Johnson, Vita Fedele, Nikiana Simigdala, Lesley-Ann Martin, Simon Andrews, Steven W Wingett, Ioannis Assiotis, Kerry Fenwick, Ritika Chauhan, Alistair G Rust, Nick Orr, Frank Dudbridge, Syed Haider, Olivia Fletcher
Genome-wide association studies (GWAS) have identified approximately 100 breast cancer risk loci. Translating these findings into a greater understanding of the mechanisms that influence disease risk requires identification of the genes or non-coding RNAs that mediate these associations. Here, we use Capture Hi-C (CHi-C) to annotate 63 loci; we identify 110 putative target genes at 33 loci. To assess the support for these target genes in other data sources we test for associations between levels of expression and SNP genotype (eQTLs), disease-specific survival (DSS), and compare them with somatically mutated cancer genes...
March 12, 2018: Nature Communications
Dong-Li Zhu, Xiao-Feng Chen, Wei-Xin Hu, Shan-Shan Dong, Bing-Jie Lu, Yu Rong, Yi-Xiao Chen, Hao Chen, Hlaing Nwe Thynn, Nai-Ning Wang, Yan Guo, Tie-Lin Yang
RANKL is a key regulator involved in bone metabolism, and a drug target for osteoporosis. The clinical diagnosis and assessment of osteoporosis are mainly based on bone mineral density (BMD). Previous powerful genome-wide association studies (GWASs) have identified multiple intergenic single nucleotide polymorphisms (SNPs) located over 100 kb upstream of RANKL and 65 kb downstream of AKAP11 at 13q14.11 for osteoporosis. Whether these SNPs exert their roles on osteoporosis through RANKL is unknown. In this study, we conducted integrative analyses combining expression quantitative trait locus (eQTL), genomic chromatin interaction (Hi-C), epigenetic annotation and a series of functional assays...
March 12, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Philipp G Maass, A Rasim Barutcu, Catherine L Weiner, John L Rinn
Imaging (fluorescence in situ hybridization [FISH]) and genome-wide chromosome conformation capture (Hi-C) are two major approaches to the study of higher-order genome organization in the nucleus. Intra-chromosomal and inter-chromosomal interactions (referred to as non-homologous chromosomal contacts [NHCCs]) have been observed by several FISH-based studies, but locus-specific NHCCs have not been detected by Hi-C. Due to crosslinking, neither of these approaches assesses spatiotemporal properties. Toward resolving the discrepancies between imaging and Hi-C, we sought to understand the spatiotemporal properties of NHCCs in living cells by CRISPR/Cas9 live-cell imaging (CLING)...
February 27, 2018: Molecular Cell
Carlo Annunziatella, Andrea M Chiariello, Andrea Esposito, Simona Bianco, Luca Fiorillo, Mario Nicodemi
In recent years interest has grown on the applications of polymer physics to model chromatin folding in order to try to make sense of the complexity of experimental data emerging from new technologies such as Hi-C or GAM, in a principled way. Here we review the methods employed to efficiently implement Molecular Dynamics computer simulations of polymer models, focusing in particular on the String&Binders Switch (SBS) model. The constant improvement of such methods and computer power is returning increasingly more accurate insights on the structure and molecular mechanisms underlying the spatial organization of chromosomes in the cell nucleus...
March 6, 2018: Methods: a Companion to Methods in Enzymology
Ibai Irastorza-Azcarate, Rafael D Acemel, Juan J Tena, Ignacio Maeso, José Luis Gómez-Skarmeta, Damien P Devos
The use of 3C-based methods has revealed the importance of the 3D organization of the chromatin for key aspects of genome biology. However, the different caveats of the variants of 3C techniques have limited their scope and the range of scientific fields that could benefit from these approaches. To address these limitations, we present 4Cin, a method to generate 3D models and derive virtual Hi-C (vHi-C) heat maps of genomic loci based on 4C-seq or any kind of 4C-seq-like data, such as those derived from NG Capture-C...
March 9, 2018: PLoS Computational Biology
Clara Lopes Novo, Biola-Maria Javierre, Jonathan Cairns, Anne Segonds-Pichon, Steven W Wingett, Paula Freire-Pritchett, Mayra Furlan-Magaril, Stefan Schoenfelder, Peter Fraser, Peter J Rugg-Gunn
Transcriptional enhancers, including super-enhancers (SEs), form physical interactions with promoters to regulate cell-type-specific gene expression. SEs are characterized by high transcription factor occupancy and large domains of active chromatin, and they are commonly assigned to target promoters using computational predictions. How promoter-SE interactions change upon cell state transitions, and whether transcription factors maintain SE interactions, have not been reported. Here, we used promoter-capture Hi-C to identify promoters that interact with SEs in mouse embryonic stem cells (ESCs)...
March 6, 2018: Cell Reports
Jialiang Huang, Kailong Li, Wenqing Cai, Xin Liu, Yuannyu Zhang, Stuart H Orkin, Jian Xu, Guo-Cheng Yuan
Recent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative analysis of Hi-C and ChIP-seq data, here we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants...
March 5, 2018: Nature Communications
Quentin Szabo, Daniel Jost, Jia-Ming Chang, Diego I Cattoni, Giorgio L Papadopoulos, Boyan Bonev, Tom Sexton, Julian Gurgo, Caroline Jacquier, Marcelo Nollmann, Frédéric Bantignies, Giacomo Cavalli
Deciphering the rules of genome folding in the cell nucleus is essential to understand its functions. Recent chromosome conformation capture (Hi-C) studies have revealed that the genome is partitioned into topologically associating domains (TADs), which demarcate functional epigenetic domains defined by combinations of specific chromatin marks. However, whether TADs are true physical units in each cell nucleus or whether they reflect statistical frequencies of measured interactions within cell populations is unclear...
February 2018: Science Advances
Robert D Stewart, Marc D Auffret, Amanda Warr, Andrew H Wiser, Maximilian O Press, Kyle W Langford, Ivan Liachko, Timothy J Snelling, Richard J Dewhurst, Alan W Walker, Rainer Roehe, Mick Watson
The cow rumen is adapted for the breakdown of plant material into energy and nutrients, a task largely performed by enzymes encoded by the rumen microbiome. Here we present 913 draft bacterial and archaeal genomes assembled from over 800 Gb of rumen metagenomic sequence data derived from 43 Scottish cattle, using both metagenomic binning and Hi-C-based proximity-guided assembly. Most of these genomes represent previously unsequenced strains and species. The draft genomes contain over 69,000 proteins predicted to be involved in carbohydrate metabolism, over 90% of which do not have a good match in public databases...
February 28, 2018: Nature Communications
Julia di Iulio, Istvan Bartha, Emily H M Wong, Hung-Chun Yu, Victor Lavrenko, Dongchan Yang, Inkyung Jung, Michael A Hicks, Naisha Shah, Ewen F Kirkness, Martin M Fabani, William H Biggs, Bing Ren, J Craig Venter, Amalio Telenti
Understanding the significance of genetic variants in the noncoding genome is emerging as the next challenge in human genomics. We used the power of 11,257 whole-genome sequences and 16,384 heptamers (7-nt motifs) to build a map of sequence constraint for the human species. This build differed substantially from traditional maps of interspecies conservation and identified regulatory elements among the most constrained regions of the genome. Using new Hi-C experimental data, we describe a strong pattern of coordination over 2 Mb where the most constrained regulatory elements associate with the most essential genes...
February 26, 2018: Nature Genetics
Oluwatosin Oluwadare, Yuxiang Zhang, Jianlin Cheng
BACKGROUND: The development of chromosomal conformation capture techniques, particularly, the Hi-C technique, has made the analysis and study of the spatial conformation of a genome an important topic in bioinformatics and computational biology. Aided by high-throughput next generation sequencing techniques, the Hi-C technique can generate genome-wide, large-scale intra- and inter-chromosomal interaction data capable of describing in details the spatial interactions within a genome. These data can be used to reconstruct 3D structures of chromosomes that can be used to study DNA replication, gene regulation, genome interaction, genome folding, and genome function...
February 23, 2018: BMC Genomics
Yan Zhang, Lin An, Jie Xu, Bo Zhang, W Jim Zheng, Ming Hu, Jijun Tang, Feng Yue
Although Hi-C technology is one of the most popular tools for studying 3D genome organization, due to sequencing cost, the resolution of most Hi-C datasets are coarse and cannot be used to link distal regulatory elements to their target genes. Here we develop HiCPlus, a computational approach based on deep convolutional neural network, to infer high-resolution Hi-C interaction matrices from low-resolution Hi-C data. We demonstrate that HiCPlus can impute interaction matrices highly similar to the original ones, while only using 1/16 of the original sequencing reads...
February 21, 2018: Nature Communications
Karim Labreche, Ben Kinnersley, Giulia Berzero, Anna Luisa Di Stefano, Amithys Rahimian, Ines Detrait, Yannick Marie, Benjamin Grenier-Boley, Khe Hoang-Xuan, Jean-Yves Delattre, Ahmed Idbaih, Richard S Houlston, Marc Sanson
Recent genome-wide association studies of glioma have led to the discovery of single nucleotide polymorphisms (SNPs) at 25 loci influencing risk. Gliomas are heterogeneous, hence to investigate the relationship between risk SNPs and glioma subtype we analysed 1659 tumours profiled for IDH mutation, TERT promoter mutation and 1p/19q co-deletion. These data allowed definition of five molecular subgroups of glioma: triple-positive (IDH mutated, 1p/19q co-deletion, TERT promoter mutated); TERT-IDH (IDH mutated, TERT promoter mutated, 1p/19q-wild-type); IDH-only (IDH mutated, 1p/19q wild-type, TERT promoter wild-type); triple-negative (IDH wild-type, 1p/19q wild-type, TERT promoter wild-type) and TERT-only (TERT promoter mutated, IDH wild-type, 1p/19q wild-type)...
February 19, 2018: Acta Neuropathologica
David Lando, Tim J Stevens, Srinjan Basu, Ernest D Laue
Single-cell chromosome conformation capture approaches are revealing the extent of cell-to-cell variability in the organization and packaging of genomes. These single-cell methods, unlike their multi-cell counterparts, allow straightforward computation of realistic chromosome conformations that may be compared and combined with other, independent, techniques to study 3D structure. Here we discuss how single-cell Hi-C and subsequent 3D genome structure determination allows comparison with data from microscopy...
February 12, 2018: Nucleus
James T Robinson, Douglass Turner, Neva C Durand, Helga Thorvaldsdóttir, Jill P Mesirov, Erez Lieberman Aiden
Contact mapping experiments such as Hi-C explore how genomes fold in 3D. Here, we introduce Juicebox.js, a cloud-based web application for exploring the resulting datasets. Like the original Juicebox application, Juicebox.js allows users to zoom in and out of such datasets using an interface similar to Google Earth. Juicebox.js also has many features designed to facilitate data reproducibility and sharing. Furthermore, Juicebox.js encodes the exact state of the browser in a shareable URL. Creating a public browser for a new Hi-C dataset does not require coding and can be accomplished in under a minute...
February 5, 2018: Cell Systems
Rubina Jibran, Helge Dzierzon, Nahla Bassil, Jill M Bushakra, Patrick P Edger, Shawn Sullivan, Chad E Finn, Michael Dossett, Kelly J Vining, Robert VanBuren, Todd C Mockler, Ivan Liachko, Kevin M Davies, Toshi M Foster, David Chagné
Black raspberry (Rubus occidentalis L.) is a niche fruit crop valued for its flavor and potential health benefits. The improvement of fruit and cane characteristics via molecular breeding technologies has been hindered by the lack of a high-quality reference genome. The recently released draft genome for black raspberry (ORUS 4115-3) lacks assembly of scaffolds to chromosome scale. We used high-throughput chromatin conformation capture (Hi-C) and Proximity-Guided Assembly (PGA) to cluster and order 9650 out of 11,936 contigs of this draft genome assembly into seven pseudo-chromosomes...
2018: Horticulture Research
Yanjian Li, Yi He, Zhengyu Liang, Yang Wang, Fengling Chen, Mohamed Nadhir Djekidel, Guipeng Li, Xu Zhang, Shuqin Xiang, Zejun Wang, Juntao Gao, Michael Q Zhang, Yang Chen
Chromatin conformation plays a key role in regulating gene expression and controlling cell differentiation. However, the whole-genome chromatin conformation changes that occur during leukemia cell differentiation are poorly understood. Here, we characterized the changes in chromatin conformation, histone states, chromatin accessibility, and gene expression using an all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation model. The results showed that the boundaries of topological associated domains (TADs) were stable during differentiation; however, the chromatin conformations within several specific TADs were obviously changed...
February 8, 2018: Cell Death & Disease
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