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ZFIN ID: ZDB-PUB-080226-13
Comparative Genomics Identifies Genes Mediating Cardiotoxicity in the Embryonic Zebrafish Heart
Chen, J., Carney, S.A., Peterson, R.E., and Heideman, W.
Date: 2008
Source: Physiological Genomics   33(2): 148-158 (Journal)
Registered Authors: Carney, Sara A., Chen, Jing, Heideman, Warren, Peterson, Richard E.
Keywords: none
Microarrays: GEO:GSE9020
MeSH Terms:
  • Animals
  • Cardiotoxins/toxicity*
  • Cell Count
  • Edema/genetics
  • Embryo, Nonmammalian/drug effects*
  • Embryo, Nonmammalian/metabolism
  • Fertilization/drug effects
  • Gene Expression Regulation, Developmental/drug effects
  • Genomics*
  • Heart/drug effects*
  • Heart/embryology*
  • Myocytes, Cardiac/drug effects
  • Myocytes, Cardiac/pathology
  • Oligonucleotide Array Sequence Analysis
  • Oligonucleotides, Antisense/pharmacology
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Reproducibility of Results
  • Time Factors
  • Tretinoin/toxicity
  • Zebrafish/embryology*
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 18230668 Full text @ Physiol. Genomics
Retinoic acid (RA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) activate distinct ligand-dependent transcription factors, and both cause cardiac malformation and heart failure in zebrafish embryos. We hypothesized that they cause this response by hyperactivating a common set of genes critical for heart development. To test this, we used microarrays to measure transcript changes in hearts isolated from zebrafish embryos 1, 2, 4, and 12 h after exposure to 1 microM RA. We used hierarchical clustering to compare the transcriptional responses produced in the embryonic heart by RA and TCDD. We could identify no early responses in common between the two agents. However, at 12 h both treatments produced a dramatic down-regulation of a common cluster of cell cycle progression genes, which we term the Cell Cycle Gene Cluster (CCGC). This was associated with a halt in heart growth. These results suggest that RA and TCDD ultimately trigger a common transcriptional response associated with heart failure, but not through the direct activation of a common set of genes. Among the genes rapidly induced by RA was Nr2F5, a member of the COUP-TF family of transcriptional repressors. We found that induction of Nr2F5 was both necessary and sufficient for the cardiotoxic response to RA. Key words: microarray, cardiotoxicity, zebrafish, TCDD, retinoic acid.