Systematic annotation of gene regulatory elements is a major challenge in genome science. Direct mapping of chromatin modification marks and transcriptional factor binding sites genome-wide has successfully identified specific subtypes of regulatory elements. In Drosophila several pioneering studies have provided genome-wide identification of Polycomb response elements, chromatin states, transcription factor binding sites, RNA polymerase II regulation and insulator elements; however, comprehensive annotation of the regulatory genome remains a significant challenge. Here we describe results from the modENCODE cis-regulatory annotation project. We produced a map of the Drosophila melanogaster regulatory genome on the basis of more than 300 chromatin immunoprecipitation data sets for eight chromatin features, five histone deacetylases and thirty-eight site-specific transcription factors at different stages of development. Using these data we inferred more than 20,000 candidate regulatory elements and validated a subset of predictions for promoters, enhancers and insulators in vivo. We identified also nearly 2,000 genomic regions of dense transcription factor binding associated with chromatin activity and accessibility. We discovered hundreds of new transcription factor co-binding relationships and defined a transcription factor network with over 800 potential regulatory relationships.
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Acknowledgements This work was supported by U01HG004264 from the National Human Genome Research Institute to K.P.W. and also funded by the Chicago Biomedical Consortiumwith supportfrom the SearleFunds at the Chicago Community Trust. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Human Genome Research Institute (NHGRI) or the National Institutes of Health (NIH). C.D.B. is supported by a Lilly-Life Sciences Research Foundation fellowship. C.A.B. is supported by a NIH NRSA postdoctoral fellowship. R.P.A. is in part supported by an Isaac Newton Trust award to R.W. P.L. was supported by a grant from the Department of Energy Computational Sciences Graduate Fellowship (DOE CSGF). M.E.L. and D.M.M. work was supported by NHGRI grant U01 HG004279. We thank the Functional Genomics Facility at the University of Chicago and the High-Throughput Genome Analysis Core at Argonne National Laboratory for processing of microarrays and of Illumina sequence. We thank T.-R. Li, J. D. Lambert, S. Rifkin, T. Herreman, C. Mason, L. Sun and Z. Gauhar for producing the developmental expression microarray data. We also thank the many members of the Drosophila community who contributed to this work by providing reagents. A complete list of community participants is included in the Supplementary Methods.