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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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Promoter Classes Are Indicative of Divergent Strategies for Transcription Initiation.The aggregation of differences in transcription factor binding sites, nucleosome organization, histone variants and chromatin marks as well as insulator elements paint a picture of divergent strategies for transcription initiation in metazoans. (A) NP promoters are marked by a ‘fuzzy’ nucleosome organization [6] (noted by alternative bulk -1 nucleosome locations in the figure) yet precise positioning of transcription initiation, which is reflected in the presence of location specific core promoter motifs that interact with a canonical TBP-containing basal complex [2], [23]. NP promoters show higher levels of pol II bound around the TSS, possibly due to an enriched presence of stalled polymerase. They are also associated with specific chromatin remodelers in fly, namely GAF. (C) Initiation events in WP promoters spread over a larger genomic span, reflected in the presence of motifs with lower positional enrichment that have been linked to remodeled basal complexes containing TRF2 in fly [60]. They exhibit a well-defined NFR and well-positioned H2A.Z nucleosomes as well as associated histone marks such as H3K4 tri-methylation. WP promoters in fly contain an enrichment of Class I insulators (CTCF, CP190, BEAF32). (B) BP promoters have a combination of features from both transcriptional programs. While chromatin organization is conserved, some of the known core promoter sequence elements depicted appear to be fly specific (Motif 1, DRE, Motif 6, Motif 7, MTE) [2], [16], [23]. Pol II and insulator proteins are depicted at the maximum binding locations; sizes of the transcriptional components are not drawn to scale.
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pgen-1001274-g008: Promoter Classes Are Indicative of Divergent Strategies for Transcription Initiation.The aggregation of differences in transcription factor binding sites, nucleosome organization, histone variants and chromatin marks as well as insulator elements paint a picture of divergent strategies for transcription initiation in metazoans. (A) NP promoters are marked by a ‘fuzzy’ nucleosome organization [6] (noted by alternative bulk -1 nucleosome locations in the figure) yet precise positioning of transcription initiation, which is reflected in the presence of location specific core promoter motifs that interact with a canonical TBP-containing basal complex [2], [23]. NP promoters show higher levels of pol II bound around the TSS, possibly due to an enriched presence of stalled polymerase. They are also associated with specific chromatin remodelers in fly, namely GAF. (C) Initiation events in WP promoters spread over a larger genomic span, reflected in the presence of motifs with lower positional enrichment that have been linked to remodeled basal complexes containing TRF2 in fly [60]. They exhibit a well-defined NFR and well-positioned H2A.Z nucleosomes as well as associated histone marks such as H3K4 tri-methylation. WP promoters in fly contain an enrichment of Class I insulators (CTCF, CP190, BEAF32). (B) BP promoters have a combination of features from both transcriptional programs. While chromatin organization is conserved, some of the known core promoter sequence elements depicted appear to be fly specific (Motif 1, DRE, Motif 6, Motif 7, MTE) [2], [16], [23]. Pol II and insulator proteins are depicted at the maximum binding locations; sizes of the transcriptional components are not drawn to scale.

Mentions: The high-throughput sequencing of 5′ capped sequence tags has clearly shown that eukaryotic promoters separate into at least two classes defined by focused and dispersed distributions of initiation events. Many recent studies have reported on the chromatin structure in eukaryotic genomes; our approach differed from most of these efforts by assessing chromatin features from the basis of transcription initiation as derived from 5′ tag data. In one exception, work concurrent to ours found differences on H3K9 acetylation based on different promoter classes [45]. Here, we have established that promoters from different classes not only contain different core promoter sequence features, but also reflect distinct patterns of nucleosome organization, chromatin structure, and insulator preferences (Figure 8).


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)

Promoter Classes Are Indicative of Divergent Strategies for Transcription Initiation.The aggregation of differences in transcription factor binding sites, nucleosome organization, histone variants and chromatin marks as well as insulator elements paint a picture of divergent strategies for transcription initiation in metazoans. (A) NP promoters are marked by a ‘fuzzy’ nucleosome organization [6] (noted by alternative bulk -1 nucleosome locations in the figure) yet precise positioning of transcription initiation, which is reflected in the presence of location specific core promoter motifs that interact with a canonical TBP-containing basal complex [2], [23]. NP promoters show higher levels of pol II bound around the TSS, possibly due to an enriched presence of stalled polymerase. They are also associated with specific chromatin remodelers in fly, namely GAF. (C) Initiation events in WP promoters spread over a larger genomic span, reflected in the presence of motifs with lower positional enrichment that have been linked to remodeled basal complexes containing TRF2 in fly [60]. They exhibit a well-defined NFR and well-positioned H2A.Z nucleosomes as well as associated histone marks such as H3K4 tri-methylation. WP promoters in fly contain an enrichment of Class I insulators (CTCF, CP190, BEAF32). (B) BP promoters have a combination of features from both transcriptional programs. While chromatin organization is conserved, some of the known core promoter sequence elements depicted appear to be fly specific (Motif 1, DRE, Motif 6, Motif 7, MTE) [2], [16], [23]. Pol II and insulator proteins are depicted at the maximum binding locations; sizes of the transcriptional components are not drawn to scale.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3020932&req=5

pgen-1001274-g008: Promoter Classes Are Indicative of Divergent Strategies for Transcription Initiation.The aggregation of differences in transcription factor binding sites, nucleosome organization, histone variants and chromatin marks as well as insulator elements paint a picture of divergent strategies for transcription initiation in metazoans. (A) NP promoters are marked by a ‘fuzzy’ nucleosome organization [6] (noted by alternative bulk -1 nucleosome locations in the figure) yet precise positioning of transcription initiation, which is reflected in the presence of location specific core promoter motifs that interact with a canonical TBP-containing basal complex [2], [23]. NP promoters show higher levels of pol II bound around the TSS, possibly due to an enriched presence of stalled polymerase. They are also associated with specific chromatin remodelers in fly, namely GAF. (C) Initiation events in WP promoters spread over a larger genomic span, reflected in the presence of motifs with lower positional enrichment that have been linked to remodeled basal complexes containing TRF2 in fly [60]. They exhibit a well-defined NFR and well-positioned H2A.Z nucleosomes as well as associated histone marks such as H3K4 tri-methylation. WP promoters in fly contain an enrichment of Class I insulators (CTCF, CP190, BEAF32). (B) BP promoters have a combination of features from both transcriptional programs. While chromatin organization is conserved, some of the known core promoter sequence elements depicted appear to be fly specific (Motif 1, DRE, Motif 6, Motif 7, MTE) [2], [16], [23]. Pol II and insulator proteins are depicted at the maximum binding locations; sizes of the transcriptional components are not drawn to scale.
Mentions: The high-throughput sequencing of 5′ capped sequence tags has clearly shown that eukaryotic promoters separate into at least two classes defined by focused and dispersed distributions of initiation events. Many recent studies have reported on the chromatin structure in eukaryotic genomes; our approach differed from most of these efforts by assessing chromatin features from the basis of transcription initiation as derived from 5′ tag data. In one exception, work concurrent to ours found differences on H3K9 acetylation based on different promoter classes [45]. Here, we have established that promoters from different classes not only contain different core promoter sequence features, but also reflect distinct patterns of nucleosome organization, chromatin structure, and insulator preferences (Figure 8).

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