title: Identification and in silico modeling of enhancers reveals new features of the cardiac differentiation network.
abstract: Developmental patterning and tissue formation are regulated through complex gene regulatory networks (GRNs) driven through the action of transcription factors (TFs) converging on enhancer elements. Here, as a point of entry to dissect the poorly defined GRN underlying cardiomyocyte differentiation, we apply an integrated approach to identify active enhancers and TFs involved in Drosophila heart development. The Drosophila heart consists of 104 cardiomyocytes, representing less than 0.5% of all cells in the embryo. By modifying BiTS-ChIP for rare cells, we examined H3K4me3 and H3K27ac chromatin landscapes to identify active promoters and enhancers specifically in cardiomyocytes. These in vivo data were complemented by a machine learning approach and extensive in vivo validation in transgenic embryos, which identified many new heart enhancers and their associated TF motifs. Our results implicate many new TFs in late stages of heart development, including Bagpipe, an Nkx3.2 ortholog, which we show is essential for differentiated heart function.
authors.affiliation: Inserm UMR_S 1090, TAGC, Parc Scientifique de Luminy, Case 908, Cedex 9, Marseille 13288, France.|Aix-Marseille Université, TAGC, Parc Scientifique de Luminy, Marseille 13288, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Seyres
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, Heidelberg 69117, Germany.
authors.forename: Yad
authors.identifier: 0000-0003-2397-9576
authors.initials: Y
authors.lastname: Ghavi-Helm
authors.affiliation: Genetic Reproduction and Development Laboratory (GReD), INSERM U1103, CNRS UMR6293, Clermont-Ferrand 63000, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Junion
authors.affiliation: Genetic Reproduction and Development Laboratory (GReD), INSERM U1103, CNRS UMR6293, Clermont-Ferrand 63000, France.
authors.forename: Ouarda
authors.initials: O
authors.lastname: Taghli-Lamallem
authors.affiliation: Inserm UMR_S 1090, TAGC, Parc Scientifique de Luminy, Case 908, Cedex 9, Marseille 13288, France.|Aix-Marseille Université, TAGC, Parc Scientifique de Luminy, Marseille 13288, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Guichard
authors.affiliation: Inserm UMR_S 1090, TAGC, Parc Scientifique de Luminy, Case 908, Cedex 9, Marseille 13288, France.|Aix-Marseille Université, TAGC, Parc Scientifique de Luminy, Marseille 13288, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Röder
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, Heidelberg 69117, Germany.
authors.forename: Charles
authors.identifier: 0000-0003-4301-3920
authors.initials: C
authors.lastname: Girardot
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstr. 1, Heidelberg 69117, Germany furlong@embl.de laurent.perrin@univ-amu.fr.
authors.forename: Eileen E M
authors.identifier: 0000-0002-9544-8339
authors.initials: EE
authors.lastname: Furlong
authors.affiliation: Inserm UMR_S 1090, TAGC, Parc Scientifique de Luminy, Case 908, Cedex 9, Marseille 13288, France furlong@embl.de laurent.perrin@univ-amu.fr.|Aix-Marseille Université, TAGC, Parc Scientifique de Luminy, Marseille 13288, France.|CNRS, Marseille 13009, France.
authors.forename: Laurent
authors.identifier: 0000-0002-4139-8743
authors.initials: L
authors.lastname: Perrin
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin; D004330:Drosophila / Q000196:embryology* / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000235:genetics; D006321:Heart / Q000196:embryology*; D006657:Histones / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology*; D038081:Organogenesis / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D002843:Chromatin; D006657:Histones; D014157:Transcription Factors
keywords: Bagpipe; Chromatin landscape; Differentiation network; Drosophila heart; Enhancer; Nkx3.2; SVM modeling