title: In Vivo Characterization of an AHR-Dependent Long Noncoding RNA Required for ProperSox9bExpression.
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 zebrafishsox9bhas 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 ofsox9bexpression 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 reducedsox9bexpression 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 thesox9bgene. We hypothesize thatslincRis regulated by AHR2 and transcriptionally repressessox9b.TheslincRtranscript functions as an RNA macromolecule, andslincRexpression is AHR2 dependent. Antisense knockdown ofslincRresults in an increase insox9bexpression during both normal development and AHR2 activation, which suggests relief in repression. During development,slincRwas expressed in tissues withsox9essential functions, including the jaw/snout region, otic vesicle, eye, and brain. Reducing the levels ofslincRresulted in altered neurologic and/or locomotor behavioral responses. Our results placeslincRas an intermediate between AHR2 activation and the reduction ofsox9bmRNA in the AHR2 signaling pathway.
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center (G.R.G., J.K.L.D., R.L.T.), and Department of Biochemistry and Biophysics (M.W.W., D.A.H), Oregon State University, Corvallis, Oregon; and Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire (B.C.G.).
authors.forename: Gloria R
authors.initials: GR
authors.lastname: Garcia
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center (G.R.G., J.K.L.D., R.L.T.), and Department of Biochemistry and Biophysics (M.W.W., D.A.H), Oregon State University, Corvallis, Oregon; and Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire (B.C.G.).
authors.forename: Britton C
authors.initials: BC
authors.lastname: Goodale
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center (G.R.G., J.K.L.D., R.L.T.), and Department of Biochemistry and Biophysics (M.W.W., D.A.H), Oregon State University, Corvallis, Oregon; and Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire (B.C.G.).
authors.forename: Michelle W
authors.initials: MW
authors.lastname: Wiley
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center (G.R.G., J.K.L.D., R.L.T.), and Department of Biochemistry and Biophysics (M.W.W., D.A.H), Oregon State University, Corvallis, Oregon; and Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire (B.C.G.).
authors.forename: Jane K
authors.initials: JK
authors.lastname: La Du
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center (G.R.G., J.K.L.D., R.L.T.), and Department of Biochemistry and Biophysics (M.W.W., D.A.H), Oregon State University, Corvallis, Oregon; and Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire (B.C.G.).
authors.forename: David A
authors.initials: DA
authors.lastname: Hendrix
authors.affiliation: Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center (G.R.G., J.K.L.D., R.L.T.), and Department of Biochemistry and Biophysics (M.W.W., D.A.H), Oregon State University, Corvallis, Oregon; and Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire (B.C.G.) robert.tanguay@oregonstate.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Tanguay
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques / Q000379:methods; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism*
chemical_list: C474372:AHR2 protein, zebrafish; D062085:RNA, Long Noncoding; D018336:Receptors, Aryl Hydrocarbon; D055758:SOX9 Transcription Factor; C504919:Sox9b protein, zebrafish; D029961:Zebrafish Proteins