Extraction of functional binding sites from unique regulatory regions: the Drosophila early developmental enhancers.
The early developmental enhancers of Drosophila melanogaster comprise one of the most sophisticated regulatory systems in higher eukaryotes. An elaborate code in their DNA sequence translates both maternal and early embryonic regulatory signals into spatial distribution of transcription factors. One of the most striking features of this code is the redundancy of binding sites for these transcription factors (BSTF). Using this redundancy, we explored the possibility of predicting functional binding sites in a single enhancer region without any prior consensus/matrix description or evolutionary sequence comparisons. We developed a conceptually simple algorithm, Scanseq, that employs an original statistical evaluation for identifying the most redundant motifs and locates the position of potential BSTF in a given regulatory region. To estimate the biological relevance of our predictions, we built thorough literature-based annotations for the best-known Drosophila developmental enhancers and we generated detailed distribution maps for the most robust binding sites. The high statistical correlation between the location of BSTF in these experiment-based maps and the location predicted in silico by Scanseq confirmed the relevance of our approach. We also discuss the definition of true binding sites and the possible biological principles that govern patterning of regulatory regions and the distribution of transcriptional signals.
Papatsenko
Dmitri A
DA
Department of Biology, New York University, New York, NY 10003-6688, USA. dap5@nyu.edu
Makeev
Vsevolod J
VJ
Lifanov
Alex P
AP
Régnier
Mireille
M
Nazina
Anna G
AG
Desplan
Claude
C
D000465:Algorithms; D000818:Animals; D001426:Bacterial Proteins; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002874:Chromosome Mapping / Q000379:methods / Q000706:statistics & numerical data; D004268:DNA-Binding Proteins / Q000235:genetics; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D017344:Genes, Insect / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics; D009687:Nuclear Proteins; D015800:Protozoan Proteins / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D020080:Tandem Repeat Sequences / Q000235:genetics; D014157:Transcription Factors
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D015800:Protozoan Proteins; D014157:Transcription Factors; C052837:eve protein, Drosophila; C080833:run protein, Drosophila