Abstract
The locations of proteins and epigenetic marks on the chromosomal DNA sequence are believed to demarcate the eukaryotic genome into distinct structural and functional domains that contribute to gene regulation and genome organization. However, how these proteins and epigenetic marks are organized in three dimensions remains unknown. Recent advances in proximity-ligation methodologies and high resolution microscopy have begun to expand our understanding of these spatial relationships. Here we use polymer models to examine the spatial organization of epigenetic marks, euchromatin and heterochromatin, and origins of replication within the Schizosaccharomyces pombe genome. These models incorporate data from microscopy and proximity-ligation experiments that inform on the positions of certain elements and contacts within and between chromosomes. Our results show a striking degree of compartmentalization of epigenetic and genomic features and lead to the proposal of a diffusion based mechanism, centred on the spindle pole body, for the coordination of DNA replication in S. pombe.
Highlights
The Schizosaccharomyces pombe genome contains a range of histone modifications associated with active (e.g. H3K4me) and inactive genes (e.g. H3K9me)[1,2,3,4]
We determined the spatial positioning of dimethylated histone H3 Lysine 4 (H3K4me2) and histone H3 Lysine 9 (H3K9me2) within the S. pombe nucleus (Fig. 1A–C,E)
Incorporation of biological restraints in the modeling procedure significantly alters the spatial distributions of these loci, indicating that nuclear confinement is insufficient for euchromatin and heterochromatin segregation and emphasizing the importance of including the chromosome contact data in the modeling procedure
Summary
Relative density maps were calculated to assess the preferred positions of different elements across the nucleus[9] These maps show the number of times that a granule to which that element has been mapped occurs at the given point within the nucleus, averaged across an ensemble of structures. Zgranule is the projection of the granule onto the SPB-nucleolus axis; and rgranule is the radial distance between the granule and axis of symmetry; zpixel and rpixel are pixel grid coordinates; wgranule is the binary signal value for the element of interest: Nstructures is the number of structures in the ensemble. We calculated the difference for each granule between the corresponding relative density maps derived for the two selected model ensembles.
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