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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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Nucleosome positioning signals may explain DNA replication efficiency.(A) Nucleosomes are depleted from origins of DNA replication in S. cerevisiae. Shown is the average number of nucleosome reads in our data (cyan) per basepair around 82 annotated origins of replication from yeast [63]. Note that the typical length of the nucleosome depleted regions is greater around replication origins than it is around transcription start sites (e.g., compare to the length of the depleted region from Figure 9A and 9B). Also shown is the average nucleosome occupancy predicted by the nucleosome positioning model that we developed here (red), per basepair around the same 82 origins. (B) Nucleosome depletion is predicted around replication origins from S. pombe. Shown is the average nucleosome occupancy predicted by our nucleosome positioning model (red), per basepair in the vicinity of 386 annotated origins of replication from S. pombe[61]. The exceptionally large length of the nucleosome depleted regions around these replication origins may reflect the lower resolution with which S. pombe origins are mapped (∼3 Kb), compared to their S. cerevisiae analogs. (C) Shown is a schematic illustration of replication origins with low and high replication efficiency. The schematic illustrates that in the low efficiency origins (“type I”, left column), binding sites for the replication machinery are measurably occupied by both their replication factors and nucleosomes (in a cell population), suggesting that their low efficiency results from competition between nucleosomes and factors for DNA access. In contrast, the high efficiency origins (“type II”, right column) exhibit a characteristic nucleosome-depleted region that allows the replication machinery to access the origins and replicate the DNA with high efficiency. (D) Replication origins from S. pombe that have large nucleosome depleted regions are utilized with greater efficiency. We computed the average (predicted) nucleosome occupancy in 500 bp windows within the 3 kb region surrounding each of the 386 annotated origins from (B). With each replication origin, we associated the lowest nucleosome occupancy in any of its 500 bp windows. The 3 kb region was selected since the data on replication efficiency have a ∼3 kb resolution [61]; 500 bp windows were selected since these are the typical lengths of the nucleosome depleted regions over origins in S. cerevisiae, where origins are mapped with greater accuracy. Using these computed lowest nucleosome occupancies for origins, we grouped together the 100 origins that have the highest of these values (type I), and the 100 origins that have the lowest of these values (type II). For each of these two groups, shown is the fraction of its origins (y-axis) whose efficiency of replication initiation as measured in [61] is within the k most efficient origins (x-axis; expressed as fraction), for all possible values of k. Measurements of efficiency of replication initiation are presented in their ranked value.
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pcbi-1000216-g013: Nucleosome positioning signals may explain DNA replication efficiency.(A) Nucleosomes are depleted from origins of DNA replication in S. cerevisiae. Shown is the average number of nucleosome reads in our data (cyan) per basepair around 82 annotated origins of replication from yeast [63]. Note that the typical length of the nucleosome depleted regions is greater around replication origins than it is around transcription start sites (e.g., compare to the length of the depleted region from Figure 9A and 9B). Also shown is the average nucleosome occupancy predicted by the nucleosome positioning model that we developed here (red), per basepair around the same 82 origins. (B) Nucleosome depletion is predicted around replication origins from S. pombe. Shown is the average nucleosome occupancy predicted by our nucleosome positioning model (red), per basepair in the vicinity of 386 annotated origins of replication from S. pombe[61]. The exceptionally large length of the nucleosome depleted regions around these replication origins may reflect the lower resolution with which S. pombe origins are mapped (∼3 Kb), compared to their S. cerevisiae analogs. (C) Shown is a schematic illustration of replication origins with low and high replication efficiency. The schematic illustrates that in the low efficiency origins (“type I”, left column), binding sites for the replication machinery are measurably occupied by both their replication factors and nucleosomes (in a cell population), suggesting that their low efficiency results from competition between nucleosomes and factors for DNA access. In contrast, the high efficiency origins (“type II”, right column) exhibit a characteristic nucleosome-depleted region that allows the replication machinery to access the origins and replicate the DNA with high efficiency. (D) Replication origins from S. pombe that have large nucleosome depleted regions are utilized with greater efficiency. We computed the average (predicted) nucleosome occupancy in 500 bp windows within the 3 kb region surrounding each of the 386 annotated origins from (B). With each replication origin, we associated the lowest nucleosome occupancy in any of its 500 bp windows. The 3 kb region was selected since the data on replication efficiency have a ∼3 kb resolution [61]; 500 bp windows were selected since these are the typical lengths of the nucleosome depleted regions over origins in S. cerevisiae, where origins are mapped with greater accuracy. Using these computed lowest nucleosome occupancies for origins, we grouped together the 100 origins that have the highest of these values (type I), and the 100 origins that have the lowest of these values (type II). For each of these two groups, shown is the fraction of its origins (y-axis) whose efficiency of replication initiation as measured in [61] is within the k most efficient origins (x-axis; expressed as fraction), for all possible values of k. Measurements of efficiency of replication initiation are presented in their ranked value.

Mentions: Finally, analogous to the cell-to-cell variability observed in gene expression [49], DNA replication origins also exhibit variability, with some origins initiating replication in most cell divisions and others initiating only occasionally. We examined whether this variability can be partly explained by differing nucleosome positioning signals in the two types of origins. In general, DNA replication origins are A/T- and Poly(dA:dT)-rich [57],[58] and thus may disfavor nucleosome formation. Indeed, we find an overall (both measured by our data and predicted by our model) nucleosome depletion around replication origins in S. cerevisiae (Figure 13A), and similar (predicted) depletion around origins in S. pombe (Figure 13B). Consistent with the hypothesis that competition with nucleosomes may affect the efficacy of replication initiation [59], a systematic sequence deletion study [60] around one replication origin in S. pombe found that deletion of a strong nucleosome-disfavoring element (Poly-A(20)) resulted in the largest reduction in replication efficiency (Figure 14). Similarly, for S. pombe, where data on efficiency of replication initiation are available [61] (such data are not available for S. cerevisiae), we find on a genome-wide scale, that replication origins with lower (predicted) nucleosome occupancy initiate replication with higher efficiency (P<10−6; Figure 13C and 13D).


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)

Nucleosome positioning signals may explain DNA replication efficiency.(A) Nucleosomes are depleted from origins of DNA replication in S. cerevisiae. Shown is the average number of nucleosome reads in our data (cyan) per basepair around 82 annotated origins of replication from yeast [63]. Note that the typical length of the nucleosome depleted regions is greater around replication origins than it is around transcription start sites (e.g., compare to the length of the depleted region from Figure 9A and 9B). Also shown is the average nucleosome occupancy predicted by the nucleosome positioning model that we developed here (red), per basepair around the same 82 origins. (B) Nucleosome depletion is predicted around replication origins from S. pombe. Shown is the average nucleosome occupancy predicted by our nucleosome positioning model (red), per basepair in the vicinity of 386 annotated origins of replication from S. pombe[61]. The exceptionally large length of the nucleosome depleted regions around these replication origins may reflect the lower resolution with which S. pombe origins are mapped (∼3 Kb), compared to their S. cerevisiae analogs. (C) Shown is a schematic illustration of replication origins with low and high replication efficiency. The schematic illustrates that in the low efficiency origins (“type I”, left column), binding sites for the replication machinery are measurably occupied by both their replication factors and nucleosomes (in a cell population), suggesting that their low efficiency results from competition between nucleosomes and factors for DNA access. In contrast, the high efficiency origins (“type II”, right column) exhibit a characteristic nucleosome-depleted region that allows the replication machinery to access the origins and replicate the DNA with high efficiency. (D) Replication origins from S. pombe that have large nucleosome depleted regions are utilized with greater efficiency. We computed the average (predicted) nucleosome occupancy in 500 bp windows within the 3 kb region surrounding each of the 386 annotated origins from (B). With each replication origin, we associated the lowest nucleosome occupancy in any of its 500 bp windows. The 3 kb region was selected since the data on replication efficiency have a ∼3 kb resolution [61]; 500 bp windows were selected since these are the typical lengths of the nucleosome depleted regions over origins in S. cerevisiae, where origins are mapped with greater accuracy. Using these computed lowest nucleosome occupancies for origins, we grouped together the 100 origins that have the highest of these values (type I), and the 100 origins that have the lowest of these values (type II). For each of these two groups, shown is the fraction of its origins (y-axis) whose efficiency of replication initiation as measured in [61] is within the k most efficient origins (x-axis; expressed as fraction), for all possible values of k. Measurements of efficiency of replication initiation are presented in their ranked value.
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Related In: Results  -  Collection

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

pcbi-1000216-g013: Nucleosome positioning signals may explain DNA replication efficiency.(A) Nucleosomes are depleted from origins of DNA replication in S. cerevisiae. Shown is the average number of nucleosome reads in our data (cyan) per basepair around 82 annotated origins of replication from yeast [63]. Note that the typical length of the nucleosome depleted regions is greater around replication origins than it is around transcription start sites (e.g., compare to the length of the depleted region from Figure 9A and 9B). Also shown is the average nucleosome occupancy predicted by the nucleosome positioning model that we developed here (red), per basepair around the same 82 origins. (B) Nucleosome depletion is predicted around replication origins from S. pombe. Shown is the average nucleosome occupancy predicted by our nucleosome positioning model (red), per basepair in the vicinity of 386 annotated origins of replication from S. pombe[61]. The exceptionally large length of the nucleosome depleted regions around these replication origins may reflect the lower resolution with which S. pombe origins are mapped (∼3 Kb), compared to their S. cerevisiae analogs. (C) Shown is a schematic illustration of replication origins with low and high replication efficiency. The schematic illustrates that in the low efficiency origins (“type I”, left column), binding sites for the replication machinery are measurably occupied by both their replication factors and nucleosomes (in a cell population), suggesting that their low efficiency results from competition between nucleosomes and factors for DNA access. In contrast, the high efficiency origins (“type II”, right column) exhibit a characteristic nucleosome-depleted region that allows the replication machinery to access the origins and replicate the DNA with high efficiency. (D) Replication origins from S. pombe that have large nucleosome depleted regions are utilized with greater efficiency. We computed the average (predicted) nucleosome occupancy in 500 bp windows within the 3 kb region surrounding each of the 386 annotated origins from (B). With each replication origin, we associated the lowest nucleosome occupancy in any of its 500 bp windows. The 3 kb region was selected since the data on replication efficiency have a ∼3 kb resolution [61]; 500 bp windows were selected since these are the typical lengths of the nucleosome depleted regions over origins in S. cerevisiae, where origins are mapped with greater accuracy. Using these computed lowest nucleosome occupancies for origins, we grouped together the 100 origins that have the highest of these values (type I), and the 100 origins that have the lowest of these values (type II). For each of these two groups, shown is the fraction of its origins (y-axis) whose efficiency of replication initiation as measured in [61] is within the k most efficient origins (x-axis; expressed as fraction), for all possible values of k. Measurements of efficiency of replication initiation are presented in their ranked value.
Mentions: Finally, analogous to the cell-to-cell variability observed in gene expression [49], DNA replication origins also exhibit variability, with some origins initiating replication in most cell divisions and others initiating only occasionally. We examined whether this variability can be partly explained by differing nucleosome positioning signals in the two types of origins. In general, DNA replication origins are A/T- and Poly(dA:dT)-rich [57],[58] and thus may disfavor nucleosome formation. Indeed, we find an overall (both measured by our data and predicted by our model) nucleosome depletion around replication origins in S. cerevisiae (Figure 13A), and similar (predicted) depletion around origins in S. pombe (Figure 13B). Consistent with the hypothesis that competition with nucleosomes may affect the efficacy of replication initiation [59], a systematic sequence deletion study [60] around one replication origin in S. pombe found that deletion of a strong nucleosome-disfavoring element (Poly-A(20)) resulted in the largest reduction in replication efficiency (Figure 14). Similarly, for S. pombe, where data on efficiency of replication initiation are available [61] (such data are not available for S. cerevisiae), we find on a genome-wide scale, that replication origins with lower (predicted) nucleosome occupancy initiate replication with higher efficiency (P<10−6; Figure 13C and 13D).

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