Mapping of Long-Range Associations throughout the Fission Yeast Genome Reveals Global Genome Organization Linked to Transcriptional Regulation

The Wistar Institute, Philadelphia, Pennsylvania, USA.
Nucleic Acids Research (Impact Factor: 9.11). 10/2010; 38(22):8164-77. DOI: 10.1093/nar/gkq955
Source: PubMed


We have comprehensively mapped long-range associations between chromosomal regions throughout the fission yeast genome using the latest genomics approach that combines next generation sequencing and chromosome conformation capture (3C). Our relatively simple approach, referred to as enrichment of ligation products (ELP), involves digestion of the 3C sample with a 4 bp cutter and self-ligation, achieving a resolution of 20 kb. It recaptures previously characterized genome organizations and also identifies new and important interactions. We have modeled the 3D structure of the entire fission yeast genome and have explored the functional relationships between the global genome organization and transcriptional regulation. We find significant associations among highly transcribed genes. Moreover, we demonstrate that genes co-regulated during the cell cycle tend to associate with one another when activated. Remarkably, functionally defined genes derived from particular gene ontology groups tend to associate in a statistically significant manner. Those significantly associating genes frequently contain the same DNA motifs at their promoter regions, suggesting that potential transcription factors binding to these motifs are involved in defining the associations among those genes. Our study suggests the presence of a global genome organization in fission yeast that is functionally similar to the recently proposed mammalian transcription factory.

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Available from: Hideki Tanizawa, Jan 15, 2014
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    • "TAD organization appears to be a conserved, but not universal phenomenon (Table 1); TADs are readily observed in Drosophila (Hou et al., 2012; Sexton et al., 2012) and mammalian (Dixon et al., 2012; Nora et al., 2012) genomes but are less clearly defined in Arabidopsis (Feng et al., 2014; Grob et al., 2014), Plasmodium falciparum (Ay et al., 2014), and yeasts (Duan et al., 2010; Tanizawa et al., 2010). Although more systematic chromatin interaction maps of different organisms are required to make further conclusions, it is interesting that species with clear TAD genomic organization match those with conservation of the insulator protein CTCF (Heger et al., 2012), further supporting its role as a genomic architectural protein. "
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    ABSTRACT: The genome must be highly compacted to fit within eukaryotic nuclei but must be accessible to the transcriptional machinery to allow appropriate expression of genes in different cell types and throughout developmental pathways. A growing body of work has shown that the genome, analogously to proteins, forms an ordered, hierarchical structure that closely correlates and may even be causally linked with regulation of functions such as transcription. This review describes our current understanding of how these functional genomic "secondary and tertiary structures" form a blueprint for global nuclear architecture and the potential they hold for understanding and manipulating genomic regulation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 03/2015; 160(6):1049-1059. DOI:10.1016/j.cell.2015.02.040 · 32.24 Impact Factor
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    • "Normalized contact count and confidence score matrices exhibit a canonical ''X'' shape, indicative of a folded chromosome architecture anchored at the centromere, as previously observed in yeast (Duan et al. 2010; Tanizawa et al. 2010) and the bacterium C. crescentus (Fig. 1C,D; Supplemental Fig. 3; Umbarger et al. 2011). However, chromosomes that harbor nonsubtelomeric clusters of genes involved in antigenic variation and immune evasion (Supplemental File 3) (VRSM genes: var, rifin, stevor and Pfmc-2tm)—chromosomes 4, 6, 7, 8, and 12—exhibit additional folding structure (Fig. 1C,D; Supplemental Fig. 3). "
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    ABSTRACT: The development of the human malaria parasite Plasmodium falciparum is controlled by coordinated changes in gene expression throughout its complex life cycle, but the corresponding regulatory mechanisms are incompletely understood. To study the relationship between genome architecture and gene regulation in Plasmodium, we assayed the genome architecture of P. falciparum at three time points during its erythrocytic (asexual) cycle. Using chromosome conformation capture coupled with next-generation sequencing technology (Hi-C), we obtained high-resolution chromosomal contact maps, which we then used to construct a consensus three-dimensional genome structure for each time point. We observed strong clustering of centromeres, telomeres, ribosomal DNA and virulence genes, resulting in a complex architecture that cannot be explained by a simple volume exclusion model. Internal virulence gene clusters exhibit domain-like structures in contact maps, suggesting that they play an important role in the genome architecture. Midway during the erythrocytic cycle, at the highly transcriptionally active trophozoite stage, the genome adopts a more open chromatin structure with increased chromosomal intermingling. In addition, we observed reduced expression of genes located in spatial proximity to the repressive subtelomeric center, and colocalization of distinct groups of parasite-specific genes with coordinated expression profiles. Overall, our results are indicative of a strong association between the P. falciparum spatial genome organization and gene expression. Understanding the molecular processes involved in genome conformation dynamics could contribute to the discovery of novel antimalarial strategies.
    Genome Research 03/2014; 24(6). DOI:10.1101/gr.169417.113 · 14.63 Impact Factor
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    • "Consequently, they simply discarded all proximal and a large portion of mid-range contacts, focusing instead on distal and interchromosomal contacts. Tanizawa et al. (2010) analyzed mid-range contacts in fission yeast by first normalizing the observed contact counts with respect to an experimental control and then correcting for random polymer looping using a double-exponential curve fitting procedure. Sexton et al. (2012) proposed a hierarchical domain model for the Drosophila genome that infers an expected chromosomal contact matrix at 10-kb resolution for each chromosome . "
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    ABSTRACT: Our current understanding of how DNA is packed in the nucleus is most accurate at the fine scale of individual nucleosomes and at the large scale of chromosome territories. However, accurate modeling of DNA architecture at the intermediate scale of ~50 kb-10 Mb is crucial for identifying functional interactions among regulatory elements and their target promoters. We describe a method, Fit-Hi-C, that assigns statistical confidence estimates to mid-range intra-chromosomal contacts by jointly modeling the random polymer looping effect and previously observed technical biases in Hi-C data sets. We demonstrate that our proposed approach computes accurate empirical null models of contact probability without any distribution assumption, corrects for binning artifacts and provides improved statistical power relative to a previously described method. High-confidence contacts identified by Fit-Hi-C preferentially link expressed gene promoters to active enhancers identified by chromatin signatures in human embryonic stem cells (ESCs), capture 77% of RNA polymerase II mediated enhancer-promoter interactions identified using ChIA-PET in mouse ESCs, and confirm previously validated, cell line-specific interactions in mouse cortex cells. Incorporating two sets of independent semi-automated genomic annotations in human ESCs, we observe that insulators and heterochromatin regions are hubs for high-confidence contacts while transcription start sites, promoters and strong enhancers are involved in fewer but potentially more targeted contacts. We also observe that regions containing binding peaks of master pluripotency factors such as NANOG and POU5F1 are highly enriched in high-confidence contacts for human ESCs. Furthermore, we show that pairs of loci linked by high-confidence contacts exhibit similar replication timing in human and mouse ESCs and preferentially lie within the boundaries of previously described topological domains for all human and mouse cell lines analyzed here.
    Genome Research 02/2014; 24(6). DOI:10.1101/gr.160374.113 · 14.63 Impact Factor
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