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Resolving the 3D landscape of transcription-linked mammalian chromatin folding

ABSTRACT: Whereas folding of mammalian genomes at the large scale of epigenomic compartments and topologically associating domains (TADs) is now relatively well-understood, how chromatin is folded below this scale remains largely unexplored in mammals. Here, we overcome this limitation using a high-resolution 3C-based method, Micro-C, and probe the links between 3D-genome organization and transcriptional regulation in mouse stem cells. Combinatorial binding of transcription factors, cofactors, and chromatin modifiers spatially segregate TAD regions into various finer-scale structures with distinct regulatory features (i.e. stripes, dots, and domains linking promoter-promoter (P-P) or enhancer-promoter (E-P), and bundle contacts between Polycomb regions). E-P stripes extending from the edge of domains predominantly link co-expressed loci, often independently of CTCF and cohesin occupancy. Acute inhibition of transcription disrupts the gene-related folding features without altering higher-order chromatin structures. Analysis of ligation events sheds light on both the putative loop extrusion model and the “two-start” zig-zag 30-nanometer model of the chromatin fiber. Our work uncovers the finer-scale genome organization that establishes novel functional links between chromatin folding and gene regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE130275 | GEO | 2019/05/21

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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Resolving the 3D landscape of transcription-linked mammalian chromatin folding

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