Dataset Information

Heterogeneous Spatial Distribution of Transcriptional Activity in Budding Yeast Nuclei.

ABSTRACT: Recent microscopic and simulation studies have shown that the genome structure fluctuates dynamically in the nuclei of budding yeast Saccharomyces cerevisiae. This genome-wide movement should lead to the fluctuations of individual genes in their territorial regions. This raises an intriguing question of whether the resulting distribution of genes is correlated to their transcriptional activity. An effective method for examining this correlation is to analyze how the spatial distribution of genes and their transcriptional activity are modified by mutation. In this study, we analyzed the modification observed in a budding yeast mutant in which genes necessary for anchoring telomeres to the nuclear envelope, yku70 and esc1, are silenced. Taddei et al. reported that 60 genes are clearly misregulated by this mutation, with 28 and 32 genes downregulated and upregulated, respectively. We calculated the probability density maps of the misregulated genes using a model of dynamical movement of the yeast genome in both wild-type (WT) and yku70 esc1 mutant and showed that the density of downregulated genes is larger near the nucleolus, whereas the density of upregulated genes is larger at the opposite side of the nucleus. By comparing these genes with those highly (top 200 of transcriptome) and lowly (bottom 200) expressed, we showed that the simulated distribution of 28 downregulated (12 out of 32 upregulated) genes has a distinctly larger overlap with the distribution of lowly (highly) expressed genes in the mutant than in the WT. The remaining 20 upregulated genes are localized near the nuclear envelope both in the WT and in the mutant. These results showed that the transcriptional level of genes is affected by their spatial distribution, thus highlighting the importance of the structural regulation in the yeast genome.

SUBMITTER: Tokuda N

PROVIDER: S-EPMC5300786 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Heterogeneous Spatial Distribution of Transcriptional Activity in Budding Yeast Nuclei.

Tokuda Naoko N Sasai Masaki M

Biophysical journal 20161228 3

Recent microscopic and simulation studies have shown that the genome structure fluctuates dynamically in the nuclei of budding yeast Saccharomyces cerevisiae. This genome-wide movement should lead to the fluctuations of individual genes in their territorial regions. This raises an intriguing question of whether the resulting distribution of genes is correlated to their transcriptional activity. An effective method for examining this correlation is to analyze how the spatial distribution of genes ...[more]

PMID: 28040197

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Project description:It is becoming increasingly clear that nuclear macromolecules and macromolecular complexes are compartmentalized through binding interactions into an apparent three-dimensionally ordered structure. This ordering, however, does not appear to be deterministic to the extent that chromatin and nonchromatin structures maintain a strict 3-D arrangement. Rather, spatial ordering within the cell nucleus appears to conform to stochastic rather than deterministic spatial relationships. The stochastic nature of organization becomes particularly problematic when any attempt is made to describe the spatial relationship between proteins involved in the regulation of the genome. The CREB-binding protein (CBP) is one such transcriptional regulator that, when visualised by confocal microscopy, reveals a highly punctate staining pattern comprising several hundred individual foci distributed within the nuclear volume. Markers for euchromatic sequences have similar patterns. Surprisingly, in most cases, the predicted one-to-one relationship between transcription factor and chromatin sequence is not observed. Consequently, to understand whether spatial relationships that are not coincident are nonrandom and potentially biologically important, it is necessary to develop statistical approaches. In this study, we report on the development of such an approach and apply it to understanding the role of CBP in mediating chromatin modification and transcriptional regulation. We have used nearest-neighbor distance measurements and probability analyses to study the spatial relationship between CBP and other nuclear subcompartments enriched in transcription factors, chromatin, and splicing factors. Our results demonstrate that CBP has an order of spatial association with other nuclear subcompartments. We observe closer associations between CBP and RNA polymerase II-enriched foci and SC35 speckles than nascent RNA or specific acetylated histones. Furthermore, we find that CBP has a significantly higher probability of being close to its known in vivo substrate histone H4 lysine 5 compared with the closely related H4 lysine 12. This study demonstrates that complex relationships not described by colocalization exist in the interphase nucleus and can be characterized and quantified. The subnuclear distribution of CBP is difficult to reconcile with a model where chromatin organization is the sole determinant of the nuclear organization of proteins that regulate transcription but is consistent with a close link between spatial associations and nuclear functions.

Dataset Information

Heterogeneous Spatial Distribution of Transcriptional Activity in Budding Yeast Nuclei.

Publications

Heterogeneous Spatial Distribution of Transcriptional Activity in Budding Yeast Nuclei.

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