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Distinct modes of regulation by chromatin encoded through nucleosome positioning signals.

Field Y, Kaplan N, Fondufe-Mittendorf Y, Moore IK, Sharon E, Lubling Y, Widom J, Segal E - PLoS Comput. Biol. (2008)

Bottom Line: The detailed positions of nucleosomes profoundly impact gene regulation and are partly encoded by the genomic DNA sequence.We find that Poly(dA:dT) tracts are an important component of these nucleosome positioning signals and that their nucleosome-disfavoring action results in large nucleosome depletion over them and over their flanking regions and enhances the accessibility of transcription factors to their cognate sites.Our results suggest that the yeast genome may utilize these nucleosome positioning signals to regulate gene expression with different transcriptional noise and activation kinetics and DNA replication with different origin efficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

ABSTRACT
The detailed positions of nucleosomes profoundly impact gene regulation and are partly encoded by the genomic DNA sequence. However, less is known about the functional consequences of this encoding. Here, we address this question using a genome-wide map of approximately 380,000 yeast nucleosomes that we sequenced in their entirety. Utilizing the high resolution of our map, we refine our understanding of how nucleosome organizations are encoded by the DNA sequence and demonstrate that the genomic sequence is highly predictive of the in vivo nucleosome organization, even across new nucleosome-bound sequences that we isolated from fly and human. We find that Poly(dA:dT) tracts are an important component of these nucleosome positioning signals and that their nucleosome-disfavoring action results in large nucleosome depletion over them and over their flanking regions and enhances the accessibility of transcription factors to their cognate sites. Our results suggest that the yeast genome may utilize these nucleosome positioning signals to regulate gene expression with different transcriptional noise and activation kinetics and DNA replication with different origin efficiency. These distinct functions may be achieved by encoding both relatively closed (nucleosome-covered) chromatin organizations over some factor binding sites, where factors must compete with nucleosomes for DNA access, and relatively open (nucleosome-depleted) organizations over other factor sites, where factors bind without competition.

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The level and length of nucleosome depletion around gene start and gene end sites correlate with boundary strength.(A) Boundaries were classified into five groups by their nucleosome fold depletion (strength) using sequence rules (see Methods), and every gene was annotated by the classification of the strongest boundary that it has in the 200 bp region upstream of its transcription start site. Shown is the average number of nucleosomes per basepair around the transcription start site of genes from each of the four boundary classification groups. (B) Same as (A), but when annotating each gene by the classification of the strongest boundary that it has in the 200 bp region downstream of its translation end site (translation end site was chosen since transcription end sites are poorly annotated). Note that for a given boundary class, the corresponding genes in (A) are distinct from the corresponding genes in (B). (C,D) Same as (A) and (B), but plotting the average nucleosome occupancy predicted by the sequence-based nucleosome positioning model that we developed here. Predictions are generated in a cross validation scheme, such that the predicted nucleosome occupancy across each chromosome is computed by a model that was learned using only the nucleosome data of all the other chromosomes.
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pcbi-1000216-g009: The level and length of nucleosome depletion around gene start and gene end sites correlate with boundary strength.(A) Boundaries were classified into five groups by their nucleosome fold depletion (strength) using sequence rules (see Methods), and every gene was annotated by the classification of the strongest boundary that it has in the 200 bp region upstream of its transcription start site. Shown is the average number of nucleosomes per basepair around the transcription start site of genes from each of the four boundary classification groups. (B) Same as (A), but when annotating each gene by the classification of the strongest boundary that it has in the 200 bp region downstream of its translation end site (translation end site was chosen since transcription end sites are poorly annotated). Note that for a given boundary class, the corresponding genes in (A) are distinct from the corresponding genes in (B). (C,D) Same as (A) and (B), but plotting the average nucleosome occupancy predicted by the sequence-based nucleosome positioning model that we developed here. Predictions are generated in a cross validation scheme, such that the predicted nucleosome occupancy across each chromosome is computed by a model that was learned using only the nucleosome data of all the other chromosomes.

Mentions: Based on the above reasoning, we hypothesized that the flanking regions of our above Poly(dA:dT) boundaries will be depleted of nucleosomes, and we expect the strength of the effect to increase with the strength of the boundary. Indeed, examining the nucleosome occupancy in the vicinity of boundaries, we find large levels of nucleosome depletion even 50 bp away from a boundary, regardless of whether or not the boundary is located close to a transcription factor binding site, and whether or not the boundary is located in a promoter region or in intergenic regions that are not promoters (Figure 7B). Moreover, examining the distribution of boundaries around transcription start sites where previous studies [5],[9],[13] found a stereotyped nucleosome depleted region, and around translation end sites where similar depletions were observed [11],[12],[26], we find that both the depletion level and length of these depleted regions strongly correlate with the boundary strength (Figure 9A and 9B). As expected, these differing nucleosome organizations around both transcription start sites and translation end sites are accurately predicted by our sequence-based model for nucleosome positioning (Figure 9C and 9D).


Distinct modes of regulation by chromatin encoded through nucleosome positioning signals.

Field Y, Kaplan N, Fondufe-Mittendorf Y, Moore IK, Sharon E, Lubling Y, Widom J, Segal E - PLoS Comput. Biol. (2008)

The level and length of nucleosome depletion around gene start and gene end sites correlate with boundary strength.(A) Boundaries were classified into five groups by their nucleosome fold depletion (strength) using sequence rules (see Methods), and every gene was annotated by the classification of the strongest boundary that it has in the 200 bp region upstream of its transcription start site. Shown is the average number of nucleosomes per basepair around the transcription start site of genes from each of the four boundary classification groups. (B) Same as (A), but when annotating each gene by the classification of the strongest boundary that it has in the 200 bp region downstream of its translation end site (translation end site was chosen since transcription end sites are poorly annotated). Note that for a given boundary class, the corresponding genes in (A) are distinct from the corresponding genes in (B). (C,D) Same as (A) and (B), but plotting the average nucleosome occupancy predicted by the sequence-based nucleosome positioning model that we developed here. Predictions are generated in a cross validation scheme, such that the predicted nucleosome occupancy across each chromosome is computed by a model that was learned using only the nucleosome data of all the other chromosomes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2570626&req=5

pcbi-1000216-g009: The level and length of nucleosome depletion around gene start and gene end sites correlate with boundary strength.(A) Boundaries were classified into five groups by their nucleosome fold depletion (strength) using sequence rules (see Methods), and every gene was annotated by the classification of the strongest boundary that it has in the 200 bp region upstream of its transcription start site. Shown is the average number of nucleosomes per basepair around the transcription start site of genes from each of the four boundary classification groups. (B) Same as (A), but when annotating each gene by the classification of the strongest boundary that it has in the 200 bp region downstream of its translation end site (translation end site was chosen since transcription end sites are poorly annotated). Note that for a given boundary class, the corresponding genes in (A) are distinct from the corresponding genes in (B). (C,D) Same as (A) and (B), but plotting the average nucleosome occupancy predicted by the sequence-based nucleosome positioning model that we developed here. Predictions are generated in a cross validation scheme, such that the predicted nucleosome occupancy across each chromosome is computed by a model that was learned using only the nucleosome data of all the other chromosomes.
Mentions: Based on the above reasoning, we hypothesized that the flanking regions of our above Poly(dA:dT) boundaries will be depleted of nucleosomes, and we expect the strength of the effect to increase with the strength of the boundary. Indeed, examining the nucleosome occupancy in the vicinity of boundaries, we find large levels of nucleosome depletion even 50 bp away from a boundary, regardless of whether or not the boundary is located close to a transcription factor binding site, and whether or not the boundary is located in a promoter region or in intergenic regions that are not promoters (Figure 7B). Moreover, examining the distribution of boundaries around transcription start sites where previous studies [5],[9],[13] found a stereotyped nucleosome depleted region, and around translation end sites where similar depletions were observed [11],[12],[26], we find that both the depletion level and length of these depleted regions strongly correlate with the boundary strength (Figure 9A and 9B). As expected, these differing nucleosome organizations around both transcription start sites and translation end sites are accurately predicted by our sequence-based model for nucleosome positioning (Figure 9C and 9D).

Bottom Line: The detailed positions of nucleosomes profoundly impact gene regulation and are partly encoded by the genomic DNA sequence.We find that Poly(dA:dT) tracts are an important component of these nucleosome positioning signals and that their nucleosome-disfavoring action results in large nucleosome depletion over them and over their flanking regions and enhances the accessibility of transcription factors to their cognate sites.Our results suggest that the yeast genome may utilize these nucleosome positioning signals to regulate gene expression with different transcriptional noise and activation kinetics and DNA replication with different origin efficiency.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.

ABSTRACT
The detailed positions of nucleosomes profoundly impact gene regulation and are partly encoded by the genomic DNA sequence. However, less is known about the functional consequences of this encoding. Here, we address this question using a genome-wide map of approximately 380,000 yeast nucleosomes that we sequenced in their entirety. Utilizing the high resolution of our map, we refine our understanding of how nucleosome organizations are encoded by the DNA sequence and demonstrate that the genomic sequence is highly predictive of the in vivo nucleosome organization, even across new nucleosome-bound sequences that we isolated from fly and human. We find that Poly(dA:dT) tracts are an important component of these nucleosome positioning signals and that their nucleosome-disfavoring action results in large nucleosome depletion over them and over their flanking regions and enhances the accessibility of transcription factors to their cognate sites. Our results suggest that the yeast genome may utilize these nucleosome positioning signals to regulate gene expression with different transcriptional noise and activation kinetics and DNA replication with different origin efficiency. These distinct functions may be achieved by encoding both relatively closed (nucleosome-covered) chromatin organizations over some factor binding sites, where factors must compete with nucleosomes for DNA access, and relatively open (nucleosome-depleted) organizations over other factor sites, where factors bind without competition.

Show MeSH
Related in: MedlinePlus