title: Cohesin-dependent globules and heterochromatin shape 3D genome architecture in S. pombe.
abstract: Eukaryotic genomes are folded into three-dimensional structures, such as self-associating topological domains, the borders of which are enriched in cohesin and CCCTC-binding factor (CTCF) required for long-range interactions. How local chromatin interactions govern higher-order folding of chromatin fibres and the function of cohesin in this process remain poorly understood. Here we perform genome-wide chromatin conformation capture (Hi-C) analysis to explore the high-resolution organization of the Schizosaccharomyces pombe genome, which despite its small size exhibits fundamental features found in other eukaryotes. Our analyses of wild-type and mutant strains reveal key elements of chromosome architecture and genome organization. On chromosome arms, small regions of chromatin locally interact to form 'globules'. This feature requires a function of cohesin distinct from its role in sister chromatid cohesion. Cohesin is enriched at globule boundaries and its loss causes disruption of local globule structures and global chromosome territories. By contrast, heterochromatin, which loads cohesin at specific sites including pericentromeric and subtelomeric domains, is dispensable for globule formation but nevertheless affects genome organization. We show that heterochromatin mediates chromatin fibre compaction at centromeres and promotes prominent inter-arm interactions within centromere-proximal regions, providing structural constraints crucial for proper genome organization. Loss of heterochromatin relaxes constraints on chromosomes, causing an increase in intra- and inter-chromosomal interactions. Together, our analyses uncover fundamental genome folding principles that drive higher-order chromosome organization crucial for coordinating nuclear functions.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology National Cancer Institute, National Institutes of Health Bethesda, MD, 20892, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: Graduate Program in Biophysics, Harvard University, Cambridge, MA, 02139, USA.|Institute for Medical Engineering and Sciences, Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Fudenberg
authors.affiliation: Laboratory of Biochemistry and Molecular Biology National Cancer Institute, National Institutes of Health Bethesda, MD, 20892, USA.
authors.forename: Sameet
authors.initials: S
authors.lastname: Mehta
authors.affiliation: Program in Systems Biology University of Massachusetts Medical School Worcester, MA, 01605, USA.
authors.forename: Jon-Matthew
authors.initials: JM
authors.lastname: Belton
authors.affiliation: Laboratory of Biochemistry and Molecular Biology National Cancer Institute, National Institutes of Health Bethesda, MD, 20892, USA.
authors.forename: Nitika
authors.initials: N
authors.lastname: Taneja
authors.affiliation: Laboratory of Biochemistry and Molecular Biology National Cancer Institute, National Institutes of Health Bethesda, MD, 20892, USA.
authors.forename: Hernan Diego
authors.initials: HD
authors.lastname: Folco
authors.affiliation: Genome Analysis Unit National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: FitzGerald
authors.affiliation: Program in Systems Biology University of Massachusetts Medical School Worcester, MA, 01605, USA.
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.affiliation: Graduate Program in Biophysics, Harvard University, Cambridge, MA, 02139, USA.|Institute for Medical Engineering and Sciences, Department of Physics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Mirny
authors.affiliation: Laboratory of Biochemistry and Molecular Biology National Cancer Institute, National Institutes of Health Bethesda, MD, 20892, USA.
authors.forename: Jemima
authors.initials: J
authors.lastname: Barrowman
authors.affiliation: Laboratory of Biochemistry and Molecular Biology National Cancer Institute, National Institutes of Health Bethesda, MD, 20892, USA.
authors.forename: Shiv I S
authors.initials: SIS
authors.lastname: Grewal
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D016681:Genome, Fungal; D006570:Heterochromatin / Q000378:metabolism*; D008968:Molecular Conformation; D012568:Schizosaccharomyces / Q000235:genetics / Q000502:physiology*; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism*; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D029702:Schizosaccharomyces pombe Proteins; D000097722:Cohesins