PUBLICATION
In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for Proper Sox9b Expression.
- Authors
- Garcia, G.R., Goodale, B.C., Wiley, M.W., La Du, J.K., Hendrix, D.A., Tanguay, R.L.
- ID
- ZDB-PUB-170408-7
- Date
- 2017
- Source
- Molecular pharmacology 91(6): 609-619 (Journal)
- Registered Authors
- La Du, Jane K., Tanguay, Robyn L.
- Keywords
- Antisense, In situ hybridization, Nuclear receptors (AHR, PXR, CAR, FXR, etc.), Regulation - xenobiotic, Regulation of gene expression
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Gene Expression Regulation, Developmental
- Gene Knockdown Techniques/methods
- RNA, Long Noncoding/biosynthesis*
- RNA, Long Noncoding/genetics*
- Receptors, Aryl Hydrocarbon/genetics*
- Receptors, Aryl Hydrocarbon/metabolism*
- SOX9 Transcription Factor/biosynthesis*
- SOX9 Transcription Factor/genetics*
- Zebrafish
- Zebrafish Proteins/biosynthesis*
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism*
- PubMed
- 28385905 Full text @ Mol. Pharmacol.
Citation
Garcia, G.R., Goodale, B.C., Wiley, M.W., La Du, J.K., Hendrix, D.A., Tanguay, R.L. (2017) In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for Proper Sox9b Expression.. Molecular pharmacology. 91(6):609-619.
Abstract
Xenobiotic activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents the proper formation of craniofacial cartilage and the heart in developing zebrafish. Downstream molecular targets responsible for AHR-dependent adverse effects remain largely unknown; however, in zebrafish sox9b has been identified as one of the most-reduced transcripts in several target organs and is hypothesized to have a causal role in TCDD-induced toxicity. The reduction of sox9b expression in TCDD-exposed zebrafish embryos has been shown to contribute to heart and jaw malformation phenotypes. The mechanisms by which AHR2 (functional ortholog of mammalian AHR) activation leads to reduced sox9b expression levels and subsequent target organ toxicity are unknown. We have identified a novel long noncoding RNA (slincR) that is upregulated by strong AHR ligands and is located adjacent to the sox9b gene. We hypothesize that slincR is regulated by AHR2 and transcriptionally represses sox9b. The slincR transcript functions as an RNA macromolecule, and slincR expression is AHR2 dependent. Antisense knockdown of slincR results in an increase in sox9b expression during both normal development and AHR2 activation, which suggests relief in repression. During development, slincR was expressed in tissues with sox9 essential functions, including the jaw/snout region, otic vesicle, eye, and brain. Reducing the levels of slincR resulted in altered neurologic and/or locomotor behavioral responses. Our results place slincR as an intermediate between AHR2 activation and the reduction of sox9b mRNA in the AHR2 signaling pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping