title: Capturing pairwise and multi-way chromosomal conformations using chromosomal walks.
abstract: Chromosomes are folded into highly compacted structures to accommodate physical constraints within nuclei and to regulate access to genomic information. Recently, global mapping of pairwise contacts showed that loops anchoring topological domains (TADs) are highly conserved between cell types and species. Whether pairwise loops synergize to form higher-order structures is still unclear. Here we develop a conformation capture assay to study higher-order organization using chromosomal walks (C-walks) that link multiple genomic loci together into proximity chains in human and mouse cells. This approach captures chromosomal structure at varying scales. Inter-chromosomal contacts constitute only 7-10% of the pairs and are restricted by interfacing TADs. About half of the C-walks stay within one chromosome, and almost half of those are restricted to intra-TAD spaces. C-walks that couple 2-4 TADs indicate stochastic associations between transcriptionally active, early replicating loci. Targeted analysis of thousands of 3-walks anchored at highly expressed genes support pairwise, rather than hub-like, chromosomal topology at active loci. Polycomb-repressed Hox domains are shown by the same approach to enrich for synergistic hubs. Together, the data indicate that chromosomal territories, TADs, and intra-TAD loops are primarily driven by nested, possibly dynamic, pairwise contacts.
authors.affiliation: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Pedro
authors.initials: P
authors.lastname: Olivares-Chauvet
authors.affiliation: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Mukamel
authors.affiliation: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Aviezer
authors.initials: A
authors.lastname: Lifshitz
authors.affiliation: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Omer
authors.initials: O
authors.lastname: Schwartzman
authors.affiliation: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Noa Oded
authors.initials: NO
authors.lastname: Elkayam
authors.affiliation: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Lubling
authors.affiliation: Icahn Institute and Dept. of Genetics &Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Gintaras
authors.initials: G
authors.lastname: Deikus
authors.affiliation: Icahn Institute and Dept. of Genetics &Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York 10029, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Sebra
authors.affiliation: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute, Rehovot 76100, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Tanay
mesh_terms: D000818:Animals; D002843:Chromatin / Q000737:chemistry / Q000235:genetics; D016386:Chromosome Walking; D002875:Chromosomes / Q000737:chemistry* / Q000235:genetics*; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D021621:Imaging, Three-Dimensional; D051379:Mice; D009690:Nucleic Acid Conformation; D063146:Polycomb-Group Proteins / Q000378:metabolism; D013269:Stochastic Processes; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D063146:Polycomb-Group Proteins