title: Occupancy by key transcription factors is a more accurate predictor of enhancer activity than histone modifications or chromatin accessibility.
abstract: BACKGROUND
  Regulated gene expression controls organismal development, and variation in regulatory patterns has been implicated in complex traits. Thus accurate prediction of enhancers is important for further understanding of these processes. Genome-wide measurement of epigenetic features, such as histone modifications and occupancy by transcription factors, is improving enhancer predictions, but the contribution of these features to prediction accuracy is not known. Given the importance of the hematopoietic transcription factor TAL1 for erythroid gene activation, we predicted candidate enhancers based on genomic occupancy by TAL1 and measured their activity. Contributions of multiple features to enhancer prediction were evaluated based on the results of these and other studies.
  
  
  RESULTS
  TAL1-bound DNA segments were active enhancers at a high rate both in transient transfections of cultured cells (39 of 79, or 56%) and transgenic mice (43 of 66, or 65%). The level of binding signal for TAL1 or GATA1 did not help distinguish TAL1-bound DNA segments as active versus inactive enhancers, nor did the density of regulation-related histone modifications. A meta-analysis of results from this and other studies (273 tested predicted enhancers) showed that the presence of TAL1, GATA1, EP300, SMAD1, H3K4 methylation, H3K27ac, and CAGE tags at DNase hypersensitive sites gave the most accurate predictors of enhancer activity, with a success rate over 80% and a median threefold increase in activity. Chromatin accessibility assays and the histone modifications H3K4me1 and H3K27ac were sensitive for finding enhancers, but they have high false positive rates unless transcription factor occupancy is also included.
  
  
  CONCLUSIONS
  Occupancy by key transcription factors such as TAL1, GATA1, SMAD1, and EP300, along with evidence of transcription, improves the accuracy of enhancer predictions based on epigenetic features.
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 304 Wartik Laboratory, University Park, PA 16802 USA.
authors.forename: Nergiz
authors.initials: N
authors.lastname: Dogan
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 304 Wartik Laboratory, University Park, PA 16802 USA ; Bioinformatics Core, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109-2218 USA.
authors.forename: Weisheng
authors.initials: W
authors.lastname: Wu
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 304 Wartik Laboratory, University Park, PA 16802 USA.
authors.forename: Christapher S
authors.initials: CS
authors.lastname: Morrissey
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 304 Wartik Laboratory, University Park, PA 16802 USA.
authors.forename: Kuan-Bei
authors.initials: KB
authors.lastname: Chen
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104 USA ; Perelman School of Medicine at the University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104 USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Stonestrom
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 304 Wartik Laboratory, University Park, PA 16802 USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Long
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 304 Wartik Laboratory, University Park, PA 16802 USA.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Keller
authors.affiliation: Department of Genetics, Mail Stop-5120, Stanford University, Stanford, CA 94305 USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 304 Wartik Laboratory, University Park, PA 16802 USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Jain
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 84-171, Berkeley, CA 94720 USA ; DOE Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, CA 94598 USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Visel
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 84-171, Berkeley, CA 94720 USA ; DOE Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, CA 94598 USA.
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.affiliation: Department of Hematology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105 USA.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, 3401 Civic Center Boulevard, Philadelphia, PA 19104 USA ; Perelman School of Medicine at the University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104 USA.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Blobel
authors.affiliation: Center for Comparative Genomics and Bioinformatics, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 304 Wartik Laboratory, University Park, PA 16802 USA.
authors.forename: Ross C
authors.initials: RC
authors.lastname: Hardison
keywords: Enhancer assay; Functional genomics; GATA1; Gene regulation; Histone modifications; TAL1