High-throughput identification of long-range regulatory elements and their target promoters in the human genome.
Title | High-throughput identification of long-range regulatory elements and their target promoters in the human genome. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Hwang, Y-C, Zheng, Q, Gregory, BD, San Wang, L- |
Journal | Nucleic Acids Res |
Volume | 41 |
Issue | 9 |
Pagination | 4835-46 |
Date Published | 2013 May |
ISSN | 1362-4962 |
Keywords | Animals, Base Sequence, Binding Sites, Conserved Sequence, DNA, Enhancer Elements, Genetic, Gene Expression, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Nucleotide Motifs, p300-CBP Transcription Factors, Promoter Regions, Genetic, RNA Polymerase II, Sequence Analysis, DNA, Vertebrates |
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. |
DOI | 10.1093/nar/gkt188 |
Alternate Journal | Nucleic Acids Res. |
PubMed ID | 23525463 |
PubMed Central ID | PMC3643598 |
Grant List | P30-AG010124 / AG / NIA NIH HHS / United States R01-GM099962 / GM / NIGMS NIH HHS / United States R01 GM099962 / GM / NIGMS NIH HHS / United States U24-AG041689 / AG / NIA NIH HHS / United States U24 AG041689 / AG / NIA NIH HHS / United States |