Integrative analysis of genomic, functional and protein interaction data predicts long-range enhancer-target gene interactions.
Multicellular organismal development is controlled by a complex network of transcription factors, promoters and enhancers. Although reliable computational and experimental methods exist for enhancer detection, prediction of their target genes remains a major challenge. On the basis of available literature and ChIP-seq and ChIP-chip data for enhanceosome factor p300 and the transcriptional regulator Gli3, we found that genomic proximity and conserved synteny predict target genes with a relatively low recall of 12-27% within 2 Mb intervals centered at the enhancers. Here, we show that functional similarities between enhancer binding proteins and their transcriptional targets and proximity in the protein-protein interactome improve prediction of target genes. We used all four features to train random forest classifiers that predict target genes with a recall of 58% in 2 Mb intervals that may contain dozens of genes, representing a better than two-fold improvement over the performance of prediction based on single features alone. Genome-wide ChIP data is still relatively poorly understood, and it remains difficult to assign biological significance to binding events. Our study represents a first step in integrating various genomic features in order to elucidate the genomic network of long-range regulatory interactions.
Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Christian
C
Rödelsperger
Gao
G
Guo
Mateusz
M
Kolanczyk
Angelika
A
Pletschacher
Sebastian
S
Köhler
Sebastian
S
Bauer
Marcel H
MH
Schulz
Peter N
PN
Robinson
D000465:Algorithms; D000818:Animals; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D023281:Genomics / Q000379:methods*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D025941:Protein Interaction Mapping / Q000379:methods*; D026801:Synteny; D000074290:Zinc Finger Protein Gli3
D004268:DNA-Binding Proteins; C465571:Gli3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3