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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aldehyde Oxidoreductases / genetics
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Aldehyde Oxidoreductases / metabolism
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Animals
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Binding Sites
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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CCAAT-Enhancer-Binding Protein-delta / genetics
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CCAAT-Enhancer-Binding Protein-delta / metabolism
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism*
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Enhancer Elements, Genetic
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Female
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Gene Expression Regulation*
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Gene Expression Regulation, Developmental
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Heart / embryology
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Heart / physiopathology*
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Male
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Mice
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Mice, Transgenic
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Models, Genetic
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Myocardial Contraction
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Myocardial Infarction / genetics*
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Myocardial Infarction / metabolism
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Myocardial Reperfusion Injury / genetics*
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Myocardial Reperfusion Injury / metabolism
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Neutrophil Infiltration
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Oligonucleotide Array Sequence Analysis
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Organ Culture Techniques
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Pericardium / cytology
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Pericardium / embryology*
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Pericardium / metabolism*
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Signal Transduction
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Uroplakin III / genetics
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Uroplakin III / metabolism
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Ventricular Remodeling
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WT1 Proteins / genetics
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WT1 Proteins / metabolism
Substances
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CCAAT-Enhancer-Binding Protein-beta
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CCAAT-Enhancer-Binding Proteins
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CEBPA protein, mouse
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Cebpb protein, mouse
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Cebpd protein, mouse
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Upk3b protein, mouse
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Uroplakin III
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WT1 Proteins
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CCAAT-Enhancer-Binding Protein-delta
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Aldehyde Oxidoreductases
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RALDH2 protein, mouse