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Transcription initiation patterns indicate divergent strategies for gene regulation at the chromatin level.

Rach EA, Winter DR, Benjamin AM, Corcoran DL, Ni T, Zhu J, Ohler U - PLoS Genet. (2011)

Bottom Line: Here, we show that promoter classes are significantly differentiated by nucleosome organization and chromatin structure.Computational models support the stronger contribution of chromatin features to the definition of dispersed promoters compared to focused start sites.Our results show that promoter classes defined from 5' capped transcripts not only reflect differences in the initiation process at the core promoter but also are indicative of divergent transcriptional programs established within gene-proximal nucleosome organization.

View Article: PubMed Central - PubMed

Affiliation: Program in Computational Biology and Bioinformatics, Duke University, Durham, North Carolina, United States of America.

ABSTRACT
The application of deep sequencing to map 5' capped transcripts has confirmed the existence of at least two distinct promoter classes in metazoans: "focused" promoters with transcription start sites (TSSs) that occur in a narrowly defined genomic span and "dispersed" promoters with TSSs that are spread over a larger window. Previous studies have explored the presence of genomic features, such as CpG islands and sequence motifs, in these promoter classes, but virtually no studies have directly investigated the relationship with chromatin features. Here, we show that promoter classes are significantly differentiated by nucleosome organization and chromatin structure. Dispersed promoters display higher associations with well-positioned nucleosomes downstream of the TSS and a more clearly defined nucleosome free region upstream, while focused promoters have a less organized nucleosome structure, yet higher presence of RNA polymerase II. These differences extend to histone variants (H2A.Z) and marks (H3K4 methylation), as well as insulator binding (such as CTCF), independent of the expression levels of affected genes. Notably, differences are conserved across mammals and flies, and they provide for a clearer separation of promoter architectures than the presence and absence of CpG islands or the occurrence of stalled RNA polymerase. Computational models support the stronger contribution of chromatin features to the definition of dispersed promoters compared to focused start sites. Our results show that promoter classes defined from 5' capped transcripts not only reflect differences in the initiation process at the core promoter but also are indicative of divergent transcriptional programs established within gene-proximal nucleosome organization.

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Related in: MedlinePlus

Heatmap of Nucleosome Occupancy within Individual Promoters.Raw H2A.Z nucleosome occupancy values for each human promoter were partitioned into the three classes. The lower panel shows the average occupancy profile across all three classes. Within each class, promoters were arranged by location of their maximum occupancy value in the range of the −1 to +1 nucleosome (−400:+250 with respect to the TSS; the diagonal pattern is thus implied by this ordering and not the data). WP and BP promoters clearly reflected the periodic H2A.Z nucleosomes flanking the NFR, especially downstream of the TSS. Between promoters, the strongest enrichments were often observed at different nucleosomes, likely due to the sparse nucleosome occupancy data.
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pgen-1001274-g002: Heatmap of Nucleosome Occupancy within Individual Promoters.Raw H2A.Z nucleosome occupancy values for each human promoter were partitioned into the three classes. The lower panel shows the average occupancy profile across all three classes. Within each class, promoters were arranged by location of their maximum occupancy value in the range of the −1 to +1 nucleosome (−400:+250 with respect to the TSS; the diagonal pattern is thus implied by this ordering and not the data). WP and BP promoters clearly reflected the periodic H2A.Z nucleosomes flanking the NFR, especially downstream of the TSS. Between promoters, the strongest enrichments were often observed at different nucleosomes, likely due to the sparse nucleosome occupancy data.

Mentions: The above analyses uncovered a clear division of promoters by nucleosome organization, quantified by different genome wide assays: dispersed promoters exhibited a clearly defined periodic nucleosome organization, whereas focused promoters were less organized at the chromatin level, ruling out the possibility that narrow initiation events were defined by tight nucleosome locations. To illustrate this in more detail, we plotted the distribution of H2A.Z nucleosomes within each promoter as a heatmap (Figure 2). Individual WP and BP promoters had more clearly defined nucleosome positions, and NP promoters displayed less organization and lower concentrations around specific locations. An unsupervised clustering of all promoters, based on bulk and H2A.Z nucleosomes, recovered these distinct nucleosome profiles, with clear enrichments for specific initiation patterns (Figure S1).


Transcription initiation patterns indicate divergent strategies for gene regulation at the chromatin level.

Rach EA, Winter DR, Benjamin AM, Corcoran DL, Ni T, Zhu J, Ohler U - PLoS Genet. (2011)

Heatmap of Nucleosome Occupancy within Individual Promoters.Raw H2A.Z nucleosome occupancy values for each human promoter were partitioned into the three classes. The lower panel shows the average occupancy profile across all three classes. Within each class, promoters were arranged by location of their maximum occupancy value in the range of the −1 to +1 nucleosome (−400:+250 with respect to the TSS; the diagonal pattern is thus implied by this ordering and not the data). WP and BP promoters clearly reflected the periodic H2A.Z nucleosomes flanking the NFR, especially downstream of the TSS. Between promoters, the strongest enrichments were often observed at different nucleosomes, likely due to the sparse nucleosome occupancy data.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3020932&req=5

pgen-1001274-g002: Heatmap of Nucleosome Occupancy within Individual Promoters.Raw H2A.Z nucleosome occupancy values for each human promoter were partitioned into the three classes. The lower panel shows the average occupancy profile across all three classes. Within each class, promoters were arranged by location of their maximum occupancy value in the range of the −1 to +1 nucleosome (−400:+250 with respect to the TSS; the diagonal pattern is thus implied by this ordering and not the data). WP and BP promoters clearly reflected the periodic H2A.Z nucleosomes flanking the NFR, especially downstream of the TSS. Between promoters, the strongest enrichments were often observed at different nucleosomes, likely due to the sparse nucleosome occupancy data.
Mentions: The above analyses uncovered a clear division of promoters by nucleosome organization, quantified by different genome wide assays: dispersed promoters exhibited a clearly defined periodic nucleosome organization, whereas focused promoters were less organized at the chromatin level, ruling out the possibility that narrow initiation events were defined by tight nucleosome locations. To illustrate this in more detail, we plotted the distribution of H2A.Z nucleosomes within each promoter as a heatmap (Figure 2). Individual WP and BP promoters had more clearly defined nucleosome positions, and NP promoters displayed less organization and lower concentrations around specific locations. An unsupervised clustering of all promoters, based on bulk and H2A.Z nucleosomes, recovered these distinct nucleosome profiles, with clear enrichments for specific initiation patterns (Figure S1).

Bottom Line: Here, we show that promoter classes are significantly differentiated by nucleosome organization and chromatin structure.Computational models support the stronger contribution of chromatin features to the definition of dispersed promoters compared to focused start sites.Our results show that promoter classes defined from 5' capped transcripts not only reflect differences in the initiation process at the core promoter but also are indicative of divergent transcriptional programs established within gene-proximal nucleosome organization.

View Article: PubMed Central - PubMed

Affiliation: Program in Computational Biology and Bioinformatics, Duke University, Durham, North Carolina, United States of America.

ABSTRACT
The application of deep sequencing to map 5' capped transcripts has confirmed the existence of at least two distinct promoter classes in metazoans: "focused" promoters with transcription start sites (TSSs) that occur in a narrowly defined genomic span and "dispersed" promoters with TSSs that are spread over a larger window. Previous studies have explored the presence of genomic features, such as CpG islands and sequence motifs, in these promoter classes, but virtually no studies have directly investigated the relationship with chromatin features. Here, we show that promoter classes are significantly differentiated by nucleosome organization and chromatin structure. Dispersed promoters display higher associations with well-positioned nucleosomes downstream of the TSS and a more clearly defined nucleosome free region upstream, while focused promoters have a less organized nucleosome structure, yet higher presence of RNA polymerase II. These differences extend to histone variants (H2A.Z) and marks (H3K4 methylation), as well as insulator binding (such as CTCF), independent of the expression levels of affected genes. Notably, differences are conserved across mammals and flies, and they provide for a clearer separation of promoter architectures than the presence and absence of CpG islands or the occurrence of stalled RNA polymerase. Computational models support the stronger contribution of chromatin features to the definition of dispersed promoters compared to focused start sites. Our results show that promoter classes defined from 5' capped transcripts not only reflect differences in the initiation process at the core promoter but also are indicative of divergent transcriptional programs established within gene-proximal nucleosome organization.

Show MeSH
Related in: MedlinePlus