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High resolution mapping of enhancer-promoter interactions.

Reeder C, Closser M, Poh HM, Sandhu K, Wichterle H, Gifford D - PLoS ONE (2015)

Bottom Line: We show that these genomic locations align more closely with features of active enhancers measured by ChIP-Seq than the locations identified using the ChIA-PET Tool.We also apply Germ to RNA Polymerase II ChIA-PET data from motor neuron progenitors.Based on the Germ results, we observe that a combination of cell type specific and cell type independent regulatory interactions are utilized by cells to regulate gene expression.

View Article: PubMed Central - PubMed

Affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

ABSTRACT
RNA Polymerase II ChIA-PET data has revealed enhancers that are active in a profiled cell type and the genes that the enhancers regulate through chromatin interactions. The most commonly used computational method for analyzing ChIA-PET data, the ChIA-PET Tool, discovers interaction anchors at a spatial resolution that is insufficient to accurately identify individual enhancers. We introduce Germ, a computational method that estimates the likelihood that any two narrowly defined genomic locations are jointly occupied by RNA Polymerase II. Germ takes a blind deconvolution approach to simultaneously estimate the likelihood of RNA Polymerase II occupation as well as a model of the arrangement of read alignments relative to locations occupied by RNA Polymerase II. Both types of information are utilized to estimate the likelihood that RNA Polymerase II jointly occupies any two genomic locations. We apply Germ to RNA Polymerase II ChIA-PET data from embryonic stem cells to identify the genomic locations that are jointly occupied along with transcription start sites. We show that these genomic locations align more closely with features of active enhancers measured by ChIP-Seq than the locations identified using the ChIA-PET Tool. We also apply Germ to RNA Polymerase II ChIA-PET data from motor neuron progenitors. Based on the Germ results, we observe that a combination of cell type specific and cell type independent regulatory interactions are utilized by cells to regulate gene expression.

No MeSH data available.


Related in: MedlinePlus

Enhancer usage reflects cell-type appropriate motif enrichment.1 kb windows centered on Med1 binding events involved in interactions with TSSs in one or both cell types were scanned for matches to known transcription factor motifs. Med1 binding events were categorized based on whether they interact with TSSs in one or both cell types. The bar graphs reflect the percentages of Med1 binding events in each group that have a motif match within 500 bp for several important transcription factors.
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pone.0122420.g008: Enhancer usage reflects cell-type appropriate motif enrichment.1 kb windows centered on Med1 binding events involved in interactions with TSSs in one or both cell types were scanned for matches to known transcription factor motifs. Med1 binding events were categorized based on whether they interact with TSSs in one or both cell types. The bar graphs reflect the percentages of Med1 binding events in each group that have a motif match within 500 bp for several important transcription factors.

Mentions: Given the evidence that we collected that indicate that the locations that Germ identifies as TSS-interacting are active enhancers, we decided to investigate whether the sequence context of Germ identified enhancers reflects their cell type specificity. We grouped the Germ identified enhancers according to their cell type utilization resulting in 2,217 enhancers that are only utilized in ESCs, 950 that are only utilized in pMNs, and 314 that are utilized in both cell types. We tested for the presence of several sequence motifs corresponding to the binding preferences of several transcription factors that are relevant to one or both cell types in 1 kb windows centered on the enhancer locations. We observed interesting patterns of motif presence for many of the factors as shown in Fig 8. The stem cell factor Klf4 [28] motif is present in almost half of the ESC enhancers, and is the most common motif present in these enhancers. Both the Klf4 and Oct4 [29] motifs are present in about twice the percentage of ESC specific enhancers as they are in pMN specific and shared enhancers. pMN specific enhancers are enriched for the RXR::RAR [30] motif and many of the Hox [31] factor motifs compared to ESC specific enhancers. Interestingly, the Sox2 [32, 33] motif is at least twice as common in enhancers specific to either cell type as in the shared enhancers. Sox2 is an important transcription factor for both cell types and it may be the case that the two cell types utilize mostly non-overlapping sets of Sox2 binding events to regulate gene expression.


High resolution mapping of enhancer-promoter interactions.

Reeder C, Closser M, Poh HM, Sandhu K, Wichterle H, Gifford D - PLoS ONE (2015)

Enhancer usage reflects cell-type appropriate motif enrichment.1 kb windows centered on Med1 binding events involved in interactions with TSSs in one or both cell types were scanned for matches to known transcription factor motifs. Med1 binding events were categorized based on whether they interact with TSSs in one or both cell types. The bar graphs reflect the percentages of Med1 binding events in each group that have a motif match within 500 bp for several important transcription factors.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430501&req=5

pone.0122420.g008: Enhancer usage reflects cell-type appropriate motif enrichment.1 kb windows centered on Med1 binding events involved in interactions with TSSs in one or both cell types were scanned for matches to known transcription factor motifs. Med1 binding events were categorized based on whether they interact with TSSs in one or both cell types. The bar graphs reflect the percentages of Med1 binding events in each group that have a motif match within 500 bp for several important transcription factors.
Mentions: Given the evidence that we collected that indicate that the locations that Germ identifies as TSS-interacting are active enhancers, we decided to investigate whether the sequence context of Germ identified enhancers reflects their cell type specificity. We grouped the Germ identified enhancers according to their cell type utilization resulting in 2,217 enhancers that are only utilized in ESCs, 950 that are only utilized in pMNs, and 314 that are utilized in both cell types. We tested for the presence of several sequence motifs corresponding to the binding preferences of several transcription factors that are relevant to one or both cell types in 1 kb windows centered on the enhancer locations. We observed interesting patterns of motif presence for many of the factors as shown in Fig 8. The stem cell factor Klf4 [28] motif is present in almost half of the ESC enhancers, and is the most common motif present in these enhancers. Both the Klf4 and Oct4 [29] motifs are present in about twice the percentage of ESC specific enhancers as they are in pMN specific and shared enhancers. pMN specific enhancers are enriched for the RXR::RAR [30] motif and many of the Hox [31] factor motifs compared to ESC specific enhancers. Interestingly, the Sox2 [32, 33] motif is at least twice as common in enhancers specific to either cell type as in the shared enhancers. Sox2 is an important transcription factor for both cell types and it may be the case that the two cell types utilize mostly non-overlapping sets of Sox2 binding events to regulate gene expression.

Bottom Line: We show that these genomic locations align more closely with features of active enhancers measured by ChIP-Seq than the locations identified using the ChIA-PET Tool.We also apply Germ to RNA Polymerase II ChIA-PET data from motor neuron progenitors.Based on the Germ results, we observe that a combination of cell type specific and cell type independent regulatory interactions are utilized by cells to regulate gene expression.

View Article: PubMed Central - PubMed

Affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

ABSTRACT
RNA Polymerase II ChIA-PET data has revealed enhancers that are active in a profiled cell type and the genes that the enhancers regulate through chromatin interactions. The most commonly used computational method for analyzing ChIA-PET data, the ChIA-PET Tool, discovers interaction anchors at a spatial resolution that is insufficient to accurately identify individual enhancers. We introduce Germ, a computational method that estimates the likelihood that any two narrowly defined genomic locations are jointly occupied by RNA Polymerase II. Germ takes a blind deconvolution approach to simultaneously estimate the likelihood of RNA Polymerase II occupation as well as a model of the arrangement of read alignments relative to locations occupied by RNA Polymerase II. Both types of information are utilized to estimate the likelihood that RNA Polymerase II jointly occupies any two genomic locations. We apply Germ to RNA Polymerase II ChIA-PET data from embryonic stem cells to identify the genomic locations that are jointly occupied along with transcription start sites. We show that these genomic locations align more closely with features of active enhancers measured by ChIP-Seq than the locations identified using the ChIA-PET Tool. We also apply Germ to RNA Polymerase II ChIA-PET data from motor neuron progenitors. Based on the Germ results, we observe that a combination of cell type specific and cell type independent regulatory interactions are utilized by cells to regulate gene expression.

No MeSH data available.


Related in: MedlinePlus