Dynamical Modeling of Three-Dimensional Genome Organization in Interphase Budding Yeast

Department of Computational Science and Engineering, Nagoya University, Nagoya, Japan.
Biophysical Journal (Impact Factor: 3.97). 01/2012; 102(2):296-304. DOI: 10.1016/j.bpj.2011.12.005
Source: PubMed


Eukaryotic genome is organized in a set of chromosomes each of which consists of a chain of DNA and associated proteins. Processes involving DNA such as transcription, duplication, and repair, therefore, should be intrinsically related to the three-dimensional organization of the genome. In this article, we develop a computational model of the three-dimensional organization of the haploid genome of interphase budding yeast by regarding chromosomes as chains moving under the constraints of nuclear structure and chromatin-chromatin interactions. The simulated genome structure largely fluctuates with the diffusive movement of chromosomes. This fluctuation, however, is not completely random, as parts of chromosomes distribute in characteristic ways to form "territories" in the nucleus. By suitably taking account of constraints arising from the data of the chromosome-conformation-capture measurement, the model explains the observed fluorescence data of chromosome distributions and motions.

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Available from: Tomoki P Terada, Jan 14, 2014
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    • "Both telomeric and centromeric regions of all yeast chromosomes group together in the nuclear space [22], [34], [35], [36]. To estimate the contribution of transcripts localized in these regions to the observed co-expression of interacting loci, we have computed the average correlations between expression profiles of genes grouped into bins according to their relative distance between the centromere and telomere. "
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    ABSTRACT: The spatial organization of eukaryotic genomes is thought to play an important role in regulating gene expression. The recent advances in experimental methods including chromatin capture techniques, as well as the large amounts of accumulated gene expression data allow studying the relationship between spatial organization of the genome and co-expression of protein-coding genes. To analyse this genome-wide relationship at a single gene resolution, we combined the interchromosomal DNA contacts in the yeast genome measured by Duan et al. with a comprehensive collection of 1,496 gene expression datasets. We find significant enhancement of co-expression among genes with contact links. The co-expression is most prominent when two gene loci fall within 1,000 base pairs from the observed contact. We also demonstrate an enrichment of inter-chromosomal links between functionally related genes, which suggests that the non random nature of the genome organization serves to facilitate coordinated transcription in groups of genes.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "If we take a time-averaged location of a specific gene, it may distribute nearly uniformly within the nucleus. However, at some time point, a specific gene should be located somewhere in a nucleus, and more importantly, it has been suggested that the spatial fluctuation of the genome is not perfectly random but possesses some ‘territory’ [62]. Therefore, we ran simulations to see the effect of localized transcription in a nucleus. "
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    ABSTRACT: Transcription factor NF-κB resides in the cytoplasm and translocates to the nucleus by application of extracellular stimuli. It is known that the nuclear NF-κB oscillates and different oscillation patterns lead to different gene expression. Nearly forty reports on modeling and simulation of nuclear NF-κB have been published to date. The computational models reported so far are temporal or two-dimensional, and the discussions on spatial parameters have not been involved or limited. Since spatial parameters in cancer cells such as nuclear to cytoplasmic volume (N/C) ratio are different from normal cells, it is important to understand the relationship between oscillation patterns and spatial parameters. Here we report simulations of a 3D computational model for the oscillation of nuclear NF-κB using A-Cell software. First, we found that the default biochemical kinetic constants used in the temporal model cannot replicate the experimentally observed oscillation in the 3D model. Thus, the default parameters should be changed in the 3D model. Second, spatial parameters such as N/C ratio, nuclear transport, diffusion coefficients, and the location of IκB synthesis were found to alter the oscillation pattern. Third, among them, larger N/C ratios resulted in persistent oscillation of nuclear NF-κB, and larger nuclear transport resulted in faster oscillation frequency. Our simulation results suggest that the changes in spatial parameters seen in cancer cells is one possible mechanism for alteration in the oscillation pattern of nuclear NF-κB and lead to the altered gene expression in these cells.
    Full-text · Article · Oct 2012 · PLoS ONE
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    Full-text · Article · Feb 2012 · Biophysical Journal
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