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      Linker histone H1.8 inhibits chromatin binding of condensins and DNA topoisomerase II to tune chromosome length and individualization

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          Abstract

          DNA loop extrusion by condensins and decatenation by DNA topoisomerase II (topo II) are thought to drive mitotic chromosome compaction and individualization. Here, we reveal that the linker histone H1.8 antagonizes condensins and topo II to shape mitotic chromosome organization. In vitro chromatin reconstitution experiments demonstrate that H1.8 inhibits binding of condensins and topo II to nucleosome arrays. Accordingly, H1.8 depletion in Xenopus egg extracts increased condensins and topo II levels on mitotic chromatin. Chromosome morphology and Hi-C analyses suggest that H1.8 depletion makes chromosomes thinner and longer through shortening the average loop size and reducing the DNA amount in each layer of mitotic loops. Furthermore, excess loading of condensins and topo II to chromosomes by H1.8 depletion causes hyper-chromosome individualization and dispersion. We propose that condensins and topo II are essential for chromosome individualization, but their functions are tuned by the linker histone to keep chromosomes together until anaphase.

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          Comprehensive mapping of long-range interactions reveals folding principles of the human genome.

          We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.
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            HiGlass: web-based visual exploration and analysis of genome interaction maps

            We present HiGlass, an open source visualization tool built on web technologies that provides a rich interface for rapid, multiplex, and multiscale navigation of 2D genomic maps alongside 1D genomic tracks, allowing users to combine various data types, synchronize multiple visualization modalities, and share fully customizable views with others. We demonstrate its utility in exploring different experimental conditions, comparing the results of analyses, and creating interactive snapshots to share with collaborators and the broader public. HiGlass is accessible online at http://higlass.io and is also available as a containerized application that can be run on any platform. Electronic supplementary material The online version of this article (10.1186/s13059-018-1486-1) contains supplementary material, which is available to authorized users.
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              Cooler: scalable storage for Hi-C data and other genomically labeled arrays

              Most existing coverage-based (epi)genomic datasets are one-dimensional, but newer technologies probing interactions (physical, genetic, etc.) produce quantitative maps with two-dimensional genomic coordinate systems. Storage and computational costs mount sharply with data resolution when such maps are stored in dense form. Hence, there is a pressing need to develop data storage strategies that handle the full range of useful resolutions in multidimensional genomic datasets by taking advantage of their sparse nature, while supporting efficient compression and providing fast random access to facilitate development of scalable algorithms for data analysis. We developed a file format called cooler, based on a sparse data model, that can support genomically labeled matrices at any resolution. It has the flexibility to accommodate various descriptions of the data axes (genomic coordinates, tracks and bin annotations), resolutions, data density patterns and metadata. Cooler is based on HDF5 and is supported by a Python library and command line suite to create, read, inspect and manipulate cooler data collections. The format has been adopted as a standard by the NIH 4D Nucleome Consortium. Cooler is cross-platform, BSD-licensed and can be installed from the Python package index or the bioconda repository. The source code is maintained on Github at https://github.com/mirnylab/cooler. Supplementary data are available at Bioinformatics online.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                18 August 2021
                2021
                : 10
                : e68918
                Affiliations
                [1 ] Laboratory of Chromosome and Cell Biology, The Rockefeller University New York United States
                [2 ] Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester United States
                [3 ] Division of Structural Biology, The Institute of Cancer Research London United Kingdom
                [4 ] Fondazione Human Technopole, Structural Biology Research Centre, 20157 Milan Italy
                [5 ] Howard Hughes Medical Institute Chevy Chase United States
                University of Edinburgh United Kingdom
                Weill Cornell Medicine United States
                University of Edinburgh United Kingdom
                University of Edinburgh United Kingdom
                Author information
                https://orcid.org/0000-0003-0387-913X
                https://orcid.org/0000-0003-3290-4293
                https://orcid.org/0000-0001-5631-0698
                https://orcid.org/0000-0003-4831-4087
                Article
                68918
                10.7554/eLife.68918
                8416026
                34406118
                ac4b2194-e273-4c8b-8762-c145ae20cbe8
                © 2021, Choppakatla et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 30 March 2021
                : 13 August 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R35 GM132111
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: R01 HG003143
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000289, Cancer Research UK;
                Award ID: CR-UK C47547/A21536
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;
                Award ID: 200818/Z/16/Z
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award ID: Investigator Program
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Chromosomes and Gene Expression
                Custom metadata
                Linker histone H1.8 shapes mitotic chromosomes by tuning the number and size of condensin-dependent DNA loops and suppressing condensin and DNA topoisomerase II-dependent individualization.

                Life sciences
                chromosome compaction,mitosis,linker histone,nucleosome,hi-c,chromatin,xenopus
                Life sciences
                chromosome compaction, mitosis, linker histone, nucleosome, hi-c, chromatin, xenopus

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