title: C/EBP transcription factors mediate epicardial activation during heart development and injury.
abstract: The epicardium encapsulates the heart and functions as a source of multipotent progenitor cells and paracrine factors essential for cardiac development and repair. Injury of the adult heart results in reactivation of a developmental gene program in the epicardium, but the transcriptional basis of epicardial gene expression has not been delineated. We established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on CCAAT/enhancer binding protein (C/EBP) transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. These findings reveal a transcriptional basis for epicardial activation and heart injury, providing a platform for enhancing cardiac regeneration.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Guo N
authors.initials: GN
authors.lastname: Huang
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Thatcher
authors.forename: John
authors.initials: J
authors.lastname: McAnally
authors.forename: Yongli
authors.initials: Y
authors.lastname: Kong
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qi
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.forename: J Michael
authors.initials: JM
authors.lastname: DiMaio
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta / Q000235:genetics / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D005260:Female; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000235:genetics* / Q000378:metabolism; D020556:Neutrophil Infiltration; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D010496:Pericardium / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D015398:Signal Transduction; D060171:Uroplakin III / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C545013:Cebpb protein, mouse; C497253:Cebpd protein, mouse; C554663:Upk3b protein, mouse; D060171:Uroplakin III; D025721:WT1 Proteins; D051743:CCAAT-Enhancer-Binding Protein-delta; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse