title: Condensin-driven remodelling of X chromosome topology during dosage compensation.
abstract: The three-dimensional organization of a genome plays a critical role in regulating gene expression, yet little is known about the machinery and mechanisms that determine higher-order chromosome structure. Here we perform genome-wide chromosome conformation capture analysis, fluorescent in situ hybridization (FISH), and RNA-seq to obtain comprehensive three-dimensional (3D) maps of the Caenorhabditis elegans genome and to dissect X chromosome dosage compensation, which balances gene expression between XX hermaphrodites and XO males. The dosage compensation complex (DCC), a condensin complex, binds to both hermaphrodite X chromosomes via sequence-specific recruitment elements on X (rex sites) to reduce chromosome-wide gene expression by half. Most DCC condensin subunits also act in other condensin complexes to control the compaction and resolution of all mitotic and meiotic chromosomes. By comparing chromosome structure in wild-type and DCC-defective embryos, we show that the DCC remodels hermaphrodite X chromosomes into a sex-specific spatial conformation distinct from autosomes. Dosage-compensated X chromosomes consist of self-interacting domains (∼1 Mb) resembling mammalian topologically associating domains (TADs). TADs on X chromosomes have stronger boundaries and more regular spacing than on autosomes. Many TAD boundaries on X chromosomes coincide with the highest-affinity rex sites and become diminished or lost in DCC-defective mutants, thereby converting the topology of X to a conformation resembling autosomes. rex sites engage in DCC-dependent long-range interactions, with the most frequent interactions occurring between rex sites at DCC-dependent TAD boundaries. These results imply that the DCC reshapes the topology of X chromosomes by forming new TAD boundaries and reinforcing weak boundaries through interactions between its highest-affinity binding sites. As this model predicts, deletion of an endogenous rex site at a DCC-dependent TAD boundary using CRISPR/Cas9 greatly diminished the boundary. Thus, the DCC imposes a distinct higher-order structure onto X chromosomes while regulating gene expression chromosome-wide.
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720-3204, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Crane
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720-3204, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Bian
authors.affiliation: Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Rachel Patton
authors.initials: RP
authors.lastname: McCord
authors.affiliation: Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Lajoie
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720-3204, USA.
authors.forename: Bayly S
authors.initials: BS
authors.lastname: Wheeler
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720-3204, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Ralston
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720-3204, USA.
authors.forename: Satoru
authors.initials: S
authors.lastname: Uzawa
authors.affiliation: Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 368 Plantation Street, Worcester, Massachusetts 01605, USA.
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.affiliation: Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, California 94720-3204, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Meyer
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004303:Dosage Compensation, Genetic / Q000235:genetics / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D017423:Sequence Analysis, RNA; D014960:X Chromosome / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C108312:condensin complexes; D000251:Adenosine Triphosphatases