title: Form and function of topologically associating genomic domains in budding yeast.
abstract: The genome of metazoan cells is organized into topologically associating domains (TADs) that have similar histone modifications, transcription level, and DNA replication timing. Although similar structures appear to be conserved in fission yeast, computational modeling and analysis of high-throughput chromosome conformation capture (Hi-C) data have been used to argue that the small, highly constrained budding yeast chromosomes could not have these structures. In contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb scale TADs, whose boundaries are enriched for transcriptional activity. Furthermore, these boundaries separate regions of similarly timed replication origins connecting the long-known effect of genomic context on replication timing to genome architecture. To investigate the molecular basis of TAD formation, we performed Hi-C experiments on cells depleted for the Forkhead transcription factors, Fkh1 and Fkh2, previously associated with replication timing. Forkhead factors do not regulate TAD formation, but do promote longer-range genomic interactions and control interactions between origins near the centromere. Thus, our work defines spatial organization within the budding yeast nucleus, demonstrates the conserved role of genome architecture in regulating DNA replication, and identifies a molecular mechanism specifically regulating interactions between pericentric origins.
authors.affiliation: Department of Applied Physics, Stanford University, Stanford, CA 94305.|Department of Genetics, Harvard Medical School, Boston, MA 02115.
authors.forename: Umut
authors.initials: U
authors.lastname: Eser
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305.
authors.forename: Devon
authors.initials: D
authors.lastname: Chandler-Brown
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195.|La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Ferhat
authors.identifier: 0000-0002-0708-6914
authors.initials: F
authors.lastname: Ay
authors.affiliation: Department of Biochemistry, Stanford University, Stanford, CA 94305.
authors.forename: Aaron F
authors.identifier: 0000-0001-5885-7881
authors.initials: AF
authors.lastname: Straight
authors.affiliation: Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109.|Division of Hematology, University of Washington School of Medicine, Seattle, WA 98195.
authors.forename: Zhijun
authors.identifier: 0000-0002-8147-793X
authors.initials: Z
authors.lastname: Duan
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195.
authors.forename: William Stafford
authors.initials: WS
authors.lastname: Noble
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305; skotheim@stanford.edu.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Skotheim
mesh_terms: D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D015825:Chromosomes, Fungal / Q000235:genetics; D042522:DNA Replication Timing; D016681:Genome, Fungal; D023281:Genomics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D004718:Saccharomycetales / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D002843:Chromatin; D029701:Saccharomyces cerevisiae Proteins
keywords: DNA replication; budding yeast; cell cycle; genome organization; systems biology