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Chromosome positioning and the clustering of functionally related loci in yeast is driven by chromosomal interactions

ABSTRACT: In recent years there has been considerable and growing interest in the 3-dimensional organization of genomes. In yeast this has included detailed FISH studies that show a surprising degree of spatial clustering of the tRNA genes, the localization of telomeres, centromere positioning, and global studies of chromosomal interactions. In this study we performed an integrated biophysical – molecular study to produce the first high-resolution 3-dimensional reconstruction of a eukaryotic genome from first principles. Our conformations were produced using a using a molecular dynamics simulator to model the 16 yeast chromosomes as individual polymers. Critically, the compaction, folding and spatial organization of these chromosomes was informed by empirical data determined using proximity-based ligation. Our models allow us to investigate the structural organization and functional spatial clustering of the yeast nucleus at a resolution that has not previously been possible. We clearly show that yeast chromosomes have preferred yet non-exclusive positions. Surprisingly, while there are general trends relating chromosome position along the spindle pole body – nucleolus axis and chromosome size, some chromosomes have territories that contain two linked domains. Similarly, there is clear evidence for functional clustering of tRNAs and Gal4 protein binding sites. Intriguingly, these functional clusters are dynamic and the identity of the component elements alters in different model solutions.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE33018 | GEO | 2012/07/19

SECONDARY ACCESSION(S): PRJNA149517

REPOSITORIES: GEO

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Project description:Eukaryotic genomes are folded into a hierarchy of three-dimensional structures that impact nuclear functions, including transcription, replication, and repair1-3. Studies in Drosophila and mammals have revealed megabase-sized topologically associated domains (TADs) within chromosomes, which in turn are spatially restricted within the nucleus4-8. However, little is known about local physical constraints that drive higher-order folding of chromosomes. Here we performed Hi-C analysis of the fission yeast Schizosaccharomyces pombe to explore genome organization at high resolution. S. pombe comprises a small genome ideal for examining structural features of chromatin folding, and contains fundamental components present in higher eukaryotes. Large domains of heterochromatin coat centromeres and telomeres and recruit cohesin, a ring-like protein complex that binds sister chromatids and mediates long range looping of interphase chromosomes. Our analyses reveal a highly ordered chromosome organization, consistent with a Rabl configuration, which is dependent on constraints imposed at centromeres and telomeres. We find that local chromatin compaction and cohesin recruitment to centromeres mediated by heterochromatin is required for maintaining global genome territorial restraint. In addition to larger complex domains, we also observed locally interacting regions of chromatin ~50 kilobases long, which organize chromosome arms into structures referred to as “globules”. Globule boundaries are enriched in cohesin and convergent gene orientation. The role of cohesin in maintaining globule domains is independent of its role in sister chromatid cohesion, as globule domains are also a feature of G1 chromosome architecture. Defect in cohesin disrupts globule domains and results in an altered chromosome organization at larger scales, including the loss of chromosome territories. Disruption of globules also affects functional annotation of the genome, leading to impairment of borders between neighboring transcriptional units. Our analyses reveal key features of chromatin organization and folding and show that distinct mechanisms uniquely impact the hierarchy of genome organization to protect genome integrity and to coordinate nuclear functions. Comparison of HiC contact maps under various conditions reveal fundamental principles of genome organization

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Chromosome positioning and the clustering of functionally related loci in yeast is driven by chromosomal interactions

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