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High-throughput identification of long-range regulatory elements and their target promoters in the human genome.

Hwang YC, Zheng Q, Gregory BD, Wang LS - Nucleic Acids Res. (2013)

Bottom Line: We observed that these promoter-interacting hotspots significantly overlap with known enhancer-associated histone modifications and DNase I hypersensitive sites.Thus, we defined thousands of candidate enhancer elements by incorporating these features, and found that they have a significant propensity to be bound by p300, an enhancer binding transcription factor.In total, our study presents a novel high-throughput workflow for confident, genome-wide discovery of enhancer-target promoter pairs, which will significantly improve our understanding of these regulatory interactions.

View Article: PubMed Central - PubMed

Affiliation: Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA, USA.

ABSTRACT
Enhancer elements are essential for tissue-specific gene regulation during mammalian development. Although these regulatory elements are often distant from their target genes, they affect gene expression by recruiting transcription factors to specific promoter regions. Because of this long-range action, the annotation of enhancer element-target promoter pairs remains elusive. Here, we developed a novel analysis methodology that takes advantage of Hi-C data to comprehensively identify these interactions throughout the human genome. To do this, we used a geometric distribution-based model to identify DNA-DNA interaction hotspots that contact gene promoters with high confidence. We observed that these promoter-interacting hotspots significantly overlap with known enhancer-associated histone modifications and DNase I hypersensitive sites. Thus, we defined thousands of candidate enhancer elements by incorporating these features, and found that they have a significant propensity to be bound by p300, an enhancer binding transcription factor. Furthermore, we revealed that their target genes are significantly bound by RNA Polymerase II and demonstrate tissue-specific expression. Finally, we uncovered that these elements are generally found within 1 Mb of their targets, and often regulate multiple genes. In total, our study presents a novel high-throughput workflow for confident, genome-wide discovery of enhancer-target promoter pairs, which will significantly improve our understanding of these regulatory interactions.

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Related in: MedlinePlus

Functional annotation of extended hotspots for sample (a) GM/HindIII, (b) GM/NcoI and (c) K562/HindIII. Each bar (as labeled) represents the percent of total length for each genomic feature that overlaps with extended hotspots.
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gkt188-F3: Functional annotation of extended hotspots for sample (a) GM/HindIII, (b) GM/NcoI and (c) K562/HindIII. Each bar (as labeled) represents the percent of total length for each genomic feature that overlaps with extended hotspots.

Mentions: We classified all extended hotspots based on human genome annotations and found that many of them are located within protein-coding genes, functional RNAs and tandem repeats, suggesting that some of the interaction hotspots may be involved in regulatory processes (Figure 3a–c). Interestingly, we observed that extended hotspots were located within 5–20% of total promoter regions (defined as the 500 bp upstream of protein-coding gene transcription start sites) of the human genome. This led us to speculate that some of the extended hotspots from our reanalysis of Hi-C data may actually reflect target promoters that are interacting with enhancer elements in the human genome.Figure 3.


High-throughput identification of long-range regulatory elements and their target promoters in the human genome.

Hwang YC, Zheng Q, Gregory BD, Wang LS - Nucleic Acids Res. (2013)

Functional annotation of extended hotspots for sample (a) GM/HindIII, (b) GM/NcoI and (c) K562/HindIII. Each bar (as labeled) represents the percent of total length for each genomic feature that overlaps with extended hotspots.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643598&req=5

gkt188-F3: Functional annotation of extended hotspots for sample (a) GM/HindIII, (b) GM/NcoI and (c) K562/HindIII. Each bar (as labeled) represents the percent of total length for each genomic feature that overlaps with extended hotspots.
Mentions: We classified all extended hotspots based on human genome annotations and found that many of them are located within protein-coding genes, functional RNAs and tandem repeats, suggesting that some of the interaction hotspots may be involved in regulatory processes (Figure 3a–c). Interestingly, we observed that extended hotspots were located within 5–20% of total promoter regions (defined as the 500 bp upstream of protein-coding gene transcription start sites) of the human genome. This led us to speculate that some of the extended hotspots from our reanalysis of Hi-C data may actually reflect target promoters that are interacting with enhancer elements in the human genome.Figure 3.

Bottom Line: We observed that these promoter-interacting hotspots significantly overlap with known enhancer-associated histone modifications and DNase I hypersensitive sites.Thus, we defined thousands of candidate enhancer elements by incorporating these features, and found that they have a significant propensity to be bound by p300, an enhancer binding transcription factor.In total, our study presents a novel high-throughput workflow for confident, genome-wide discovery of enhancer-target promoter pairs, which will significantly improve our understanding of these regulatory interactions.

View Article: PubMed Central - PubMed

Affiliation: Genomics and Computational Biology Graduate Program, University of Pennsylvania, Philadelphia, PA, USA.

ABSTRACT
Enhancer elements are essential for tissue-specific gene regulation during mammalian development. Although these regulatory elements are often distant from their target genes, they affect gene expression by recruiting transcription factors to specific promoter regions. Because of this long-range action, the annotation of enhancer element-target promoter pairs remains elusive. Here, we developed a novel analysis methodology that takes advantage of Hi-C data to comprehensively identify these interactions throughout the human genome. To do this, we used a geometric distribution-based model to identify DNA-DNA interaction hotspots that contact gene promoters with high confidence. We observed that these promoter-interacting hotspots significantly overlap with known enhancer-associated histone modifications and DNase I hypersensitive sites. Thus, we defined thousands of candidate enhancer elements by incorporating these features, and found that they have a significant propensity to be bound by p300, an enhancer binding transcription factor. Furthermore, we revealed that their target genes are significantly bound by RNA Polymerase II and demonstrate tissue-specific expression. Finally, we uncovered that these elements are generally found within 1 Mb of their targets, and often regulate multiple genes. In total, our study presents a novel high-throughput workflow for confident, genome-wide discovery of enhancer-target promoter pairs, which will significantly improve our understanding of these regulatory interactions.

Show MeSH
Related in: MedlinePlus