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Accession IconSRP078520

Altered basal and TCDD-induced gene expression in zebrafish embryos made AHRRa-null by ZFN-mediated gene targeting

Organism Icon Danio rerio
Sample Icon 14 Downloadable Samples
Technology Badge IconIllumina HiSeq 2000

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The aryl hydrocarbon receptor (AHR) repressor (AHRR), a bHLH-PAS protein, is a transcriptional repressor of AHR and other transcription factors (HIF, ER) and is regulated by an AHR-dependent mechanism. However, the physiological and toxicological roles of AHRR are not well understood. We demonstrated earlier that knockdown of AHRRa (one of two AHRR paralogs) in zebrafish embryos using morpholino anti-sense oligonucleotides results in developmental phenotypes such as pericardial edema, craniofacial malformations, and cardiac deformities, similar to effects caused by exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AHRRa morphants also exhibit down-regulation of genes associated with photoreceptor development. To characterize the AHRRa function further, we used ZFN (zinc finger nuclease) technology to generate a line of zebrafish with a 7-bp deletion in exon 3 of AHRRa, leading to a truncated AHRR (110 aa, of which 38 are from AHRRa, compared to the 550-aa wild-type (wt) AHRRa). The mutant AHRRa protein, which contains basic regions but lacks the HLH and PAS domains, did not repress AHR in vitro, suggesting that it is inactive (null). Unlike AHRRa morphants, AHRRa-null fish did not display a TCDD-like phenotype; exposure to TCDD caused defects similar to those in TCDD-exposed wt embryos. RNA-sequencing revealed that basal expression of 562 genes differed significantly between the null and wt embryos, including down-regulation of genes associated with photoreceptor development, as seen in AHRRa morphants. TCDD-induced gene expression patterns for the prototypic AHR target genes were similar for null and wt embryos. However, 22 genes were differentially regulated by TCDD in the AHRRa-null embryos as compared to wt embryos (>2-fold; 5% FDR). We are currently investigating the link between these differentially expressed genes and the function of AHRRa in development and AHR signaling. [Supported by NIH R01ES006272] Overall design: Ahrra-null and wild type embryos were exposed to either solvent control or 2nM TCDD for 1 hour at 6 hours post-fertilization and subsequently reared in clean water until 72 hpf. At 72 hpf, embryos were sampled for gene expression profiling.
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