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An Overview of Methods for Reconstructing 3-D Chromosome and Genome Structures from Hi-C Data

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      Abstract

      Over the past decade, methods for predicting three-dimensional (3-D) chromosome and genome structures have proliferated. This has been primarily due to the development of high-throughput, next-generation chromosome conformation capture (3C) technologies, which have provided next-generation sequencing data about chromosome conformations in order to map the 3-D genome structure. The introduction of the Hi-C technique—a variant of the 3C method—has allowed researchers to extract the interaction frequency (IF) for all loci of a genome at high-throughput and at a genome-wide scale. In this review we describe, categorize, and compare the various methods developed to map chromosome and genome structures from 3C data—particularly Hi-C data. We summarize the improvements introduced by these methods, describe the approach used for method evaluation, and discuss how these advancements shape the future of genome structure construction.

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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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        Imaging intracellular fluorescent proteins at nanometer resolution.

        We introduce a method for optically imaging intracellular proteins at nanometer spatial resolution. Numerous sparse subsets of photoactivatable fluorescent protein molecules were activated, localized (to approximately 2 to 25 nanometers), and then bleached. The aggregate position information from all subsets was then assembled into a superresolution image. We used this method--termed photoactivated localization microscopy--to image specific target proteins in thin sections of lysosomes and mitochondria; in fixed whole cells, we imaged vinculin at focal adhesions, actin within a lamellipodium, and the distribution of the retroviral protein Gag at the plasma membrane.
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          Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM).

          We have developed a high-resolution fluorescence microscopy method based on high-accuracy localization of photoswitchable fluorophores. In each imaging cycle, only a fraction of the fluorophores were turned on, allowing their positions to be determined with nanometer accuracy. The fluorophore positions obtained from a series of imaging cycles were used to reconstruct the overall image. We demonstrated an imaging resolution of 20 nm. This technique can, in principle, reach molecular-scale resolution.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 2162 3504, GRID grid.134936.a, Department of Electrical Engineering and Computer Science, , University of Missouri, ; Columbia, MO 65211 USA
            [2 ]ISNI 0000 0001 2162 3504, GRID grid.134936.a, Informatics Institute, , University of Missouri, ; Columbia, MO 65211 USA
            Contributors
            oeow39@mail.missouri.edu
            mrh8x5@mail.missouri.edu
            ORCID: http://orcid.org/0000-0003-0305-2853, chengji@missouri.edu
            Journal
            Biol Proced Online
            Biol Proced Online
            Biological Procedures Online
            BioMed Central (London )
            1480-9222
            24 April 2019
            24 April 2019
            2019
            : 21
            6482566
            94
            10.1186/s12575-019-0094-0
            © The Author(s). 2019

            Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

            Funding
            Funded by: FundRef http://dx.doi.org/10.13039/100000001, National Science Foundation;
            Award ID: DBI1149224
            Award Recipient :
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            © The Author(s) 2019

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