Comparative Genomics Identifies Gene Targets for Retinoic Acid in the Embryonic Zebrafish Hearts

Retinoic acid (RA) and 2,3,7,8-tetrachlorodibenzo-p-dioxin 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 transcripts changes in hearts isolated from zebrafish embryos 1,2,4 and 12 h after exposure to 1M 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 downregulation 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 transcription repressors. We found that induction of Nr2F5 was both necessary and sufficient for the cardiotoxic response to RA.

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Chen J, Carney SA, Peterson RE, Heideman W