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Knockdown of a zebrafish aryl hydrocarbon receptor repressor (ahrra) affects expression of genes related to photoreceptor development and hematopoiesis.

ABSTRACT: The aryl hydrocarbon receptor repressor (AHRR) is a bHLH-PAS protein closely related to the aryl hydrocarbon receptor (AHR). AHRR is a transcriptional repressor of AHR and hypoxia-inducible factor (HIF) and is regulated by an AHR-dependent mechanism. Zebrafish possess two AHRR paralogs; AHRRa regulates constitutive AHR signaling during development, while AHRRb regulates polyaromatic hydrocarbon-induced gene expression. However, very little is known about the endogenous roles of AHRRs in development and physiology. The objective of this study was to elucidate the role of AHRRs during zebrafish development using a loss-of-function approach followed by microarray analysis. Zebrafish embryos were microinjected with morpholino oligonucleotides (MO) against AHRRa or AHRRb to disrupt endogenous signaling during development. At 72 hours post-fertilization (hpf), embryos were sampled for microarray analysis. Agilent microarray analysis revealed altered expression of 279 and 116 genes with knockdown of AHRRa and AHRRb, respectively. In AHRRa-morphant embryos, 97 genes were up-regulated and 182 genes were down-regulated. Among the differentially expressed genes were a large number related to photoreceptor development, including cone-specific genes such as short-wave, medium-wave and long-wave sensitive opsins (opn1sw1, opn1sw2, opn1mw1, opn1lw2), phosphodiesterases (pde6H, pde6C), retinol binding protein (rbp4l), phosducin, and arrestin. These results suggest that AHRRa may be involved in photoreceptor development. In addition, AHRRa knockdown also caused up-regulation of embryonic hemoglobin (hbbe3), suggesting a role for AHRR in regulating hematopoiesis. Knockdown of AHRRb caused up-regulation of 31 genes and down-regulation of 85 genes, without enrichment of genes related to any specific biological process. Overall, these results suggest that AHRRs play multiple roles during development.

ORGANISM(S): Danio rerio

PROVIDER: GSE52229 | GEO | 2014/01/15

SECONDARY ACCESSION(S): PRJNA227196

REPOSITORIES: GEO

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Project description:The aryl hydrocarbon receptor repressor (AHRR) is a bHLH-PAS protein closely related to the aryl hydrocarbon receptor (AHR). AHRR is a transcriptional repressor of AHR and hypoxia-inducible factor (HIF) and is regulated by an AHR-dependent mechanism. Zebrafish possess two AHRR paralogs; AHRRa regulates constitutive AHR signaling during development, while AHRRb regulates polyaromatic hydrocarbon-induced gene expression. However, very little is known about the endogenous roles of AHRRs in development and physiology. The objective of this study was to elucidate the role of AHRRs during zebrafish development using a loss-of-function approach followed by microarray analysis. Zebrafish embryos were microinjected with morpholino oligonucleotides (MO) against AHRRa or AHRRb to disrupt endogenous signaling during development. At 72 hours post-fertilization (hpf), embryos were sampled for microarray analysis. Agilent microarray analysis revealed altered expression of 279 and 116 genes with knockdown of AHRRa and AHRRb, respectively. In AHRRa-morphant embryos, 97 genes were up-regulated and 182 genes were down-regulated. Among the differentially expressed genes were a large number related to photoreceptor development, including cone-specific genes such as short-wave, medium-wave and long-wave sensitive opsins (opn1sw1, opn1sw2, opn1mw1, opn1lw2), phosphodiesterases (pde6H, pde6C), retinol binding protein (rbp4l), phosducin, and arrestin. These results suggest that AHRRa may be involved in photoreceptor development. In addition, AHRRa knockdown also caused up-regulation of embryonic hemoglobin (hbbe3), suggesting a role for AHRR in regulating hematopoiesis. Knockdown of AHRRb caused up-regulation of 31 genes and down-regulation of 85 genes, without enrichment of genes related to any specific biological process. Overall, these results suggest that AHRRs play multiple roles during development. Three different treatment conditions (Control-MO, AHRRa-MO and AHRRb-MO) and two replicates per treatment

Project description:Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment as components of fossil fuels and by-products of combustion. These multi-ring chemicals differentially activate the Aryl Hydrocarbon Receptor (AHR) in a structurally-dependent manner, and induce toxicity via both AHR-dependent and -independent mechanisms. PAH exposure is known to induce developmental malformations in zebrafish embryos, and recent studies have shown cardiac toxicity induced by compounds with low AHR affinity. Unraveling the potentially diverse molecular mechanisms of PAH toxicity is essential for understanding the hazard posed by complex PAH mixtures present in the environment. We analyzed transcriptional responses to PAH exposure in zebrafish embryos exposed to benz(a)anthracene (BAA), dibenzothiophene (DBT) and pyrene (PYR) at a concentration that induces developmental malformations by 120 hours post-fertilization (hpf). Whole genome microarray analysis of mRNA expression at 24 and 48 hpf identified genes that were differentially regulated over time and in response to the three PAH structures. PAH body burden was analyzed at these time points using GC-MS, and demonstrated differences in PAH uptake into the embryos. This was important for discerning dose-related differences from those that represented unique molecular mechanisms. While BAA misregulated the smallest number of transcripts, it caused strong induction of cyp1a and other genes known to be downstream of the AHR, which were not induced by the other two PAHs. Analysis of functional roles of misregulated genes and their predicted regulatory transcription factors also distinguished the BAA response from regulatory networks disrupted by DBT and PYR exposure. These results indicate that systems approaches can be used to classify the toxicity of PAHs based on the networks perturbed following exposure and may provide a path for unraveling the toxicity of complex PAH mixtures. Gene expression was measured in zebrafish embryos after exposure to PAHs. Embryos were batch-exposed in groups of 40 to 25 μM BAA, 25 μM DBT, 25 μM PYR or 1% DMSO vehicle control starting at 6 hpf and collected at 24 or 48 hpf. Four independent biological replicates were prepared for each treatment. The reference was a pool of zebrafish embryos exposed to DMSO control until 24 and 48 hpf.

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Knockdown of a zebrafish aryl hydrocarbon receptor repressor (ahrra) affects expression of genes related to photoreceptor development and hematopoiesis.

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