Combinatorial binding predicts spatio-temporal cis-regulatory activity.
Development requires the establishment of precise patterns of gene expression, which are primarily controlled by transcription factors binding to cis-regulatory modules. Although transcription factor occupancy can now be identified at genome-wide scales, decoding this regulatory landscape remains a daunting challenge. Here we used a novel approach to predict spatio-temporal cis-regulatory activity based only on in vivo transcription factor binding and enhancer activity data. We generated a high-resolution atlas of cis-regulatory modules describing their temporal and combinatorial occupancy during Drosophila mesoderm development. The binding profiles of cis-regulatory modules with characterized expression were used to train support vector machines to predict five spatio-temporal expression patterns. In vivo transgenic reporter assays demonstrate the high accuracy of these predictions and reveal an unanticipated plasticity in transcription factor binding leading to similar expression. This data-driven approach does not require previous knowledge of transcription factor sequence affinity, function or expression, making it widely applicable.
Zinzen
Robert P
RP
European Molecular Biology Laboratory, D-69117 Heidelberg, Germany.
Girardot
Charles
C
Gagneur
Julien
J
Braun
Martina
M
Furlong
Eileen E M
EE
D000818:Animals; D030801:Animals, Genetically Modified; D001185:Artificial Intelligence; D047369:Chromatin Immunoprecipitation; D017124:Conserved Sequence / Q000235:genetics; D030541:Databases, Genetic; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D008957:Models, Genetic; D011485:Protein Binding; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
D014157:Transcription Factors