title: Population-based 3D genome structure analysis reveals driving forces in spatial genome organization.
abstract: Conformation capture technologies (e.g., Hi-C) chart physical interactions between chromatin regions on a genome-wide scale. However, the structural variability of the genome between cells poses a great challenge to interpreting ensemble-averaged Hi-C data, particularly for long-range and interchromosomal interactions. Here, we present a probabilistic approach for deconvoluting Hi-C data into a model population of distinct diploid 3D genome structures, which facilitates the detection of chromatin interactions likely to co-occur in individual cells. Our approach incorporates the stochastic nature of chromosome conformations and allows a detailed analysis of alternative chromatin structure states. For example, we predict and experimentally confirm the presence of large centromere clusters with distinct chromosome compositions varying between individual cells. The stability of these clusters varies greatly with their chromosome identities. We show that these chromosome-specific clusters can play a key role in the overall chromosome positioning in the nucleus and stabilizing specific chromatin interactions. By explicitly considering genome structural variability, our population-based method provides an important tool for revealing novel insights into the key factors shaping the spatial genome organization.
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Harianto
authors.identifier: http://orcid.org/0000-0001-7992-2697
authors.initials: H
authors.lastname: Tjong
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Li
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Reza
authors.initials: R
authors.lastname: Kalhor
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Chao
authors.initials: C
authors.lastname: Dai
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Shengli
authors.initials: S
authors.lastname: Hao
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Ke
authors.initials: K
authors.lastname: Gong
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Haochen
authors.initials: H
authors.lastname: Li
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089;
authors.forename: Xianghong Jasmine
authors.initials: XJ
authors.lastname: Zhou
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94148; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94702; National Center for X-Ray Tomography, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94702;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Le Gros
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94148; Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94702; National Center for X-Ray Tomography, Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, CA 94702;
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Larabell
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Department of Chemistry and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; alber@usc.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Alber
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002460:Cell Line; D002503:Centromere / Q000648:ultrastructure; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D045584:Chromosome Positioning; D002875:Chromosomes / Q000235:genetics / Q000648:ultrastructure*; D002877:Chromosomes, Human / Q000235:genetics / Q000648:ultrastructure; D004171:Diploidy; D015894:Genome, Human; D006570:Heterochromatin / Q000648:ultrastructure; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods*; D017404:In Situ Hybridization, Fluorescence; D016013:Likelihood Functions; D008214:Lymphocytes / Q000648:ultrastructure; D056186:Metagenomics / Q000379:methods*; D011323:Primates / Q000235:genetics; D059010:Single-Cell Analysis; D013269:Stochastic Processes; D014056:Tomography, X-Ray / Q000379:methods
chemical_list: D002843:Chromatin; D006570:Heterochromatin
keywords: 3D genome organization; Hi-C data analysis; centromere clustering; genome structure modeling; human genome