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Key Event Title
Increase, slincR expression
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Ahr mediated early stage mortality via craniofacial malformations||KeyEvent||Prarthana Shankar (send email)||Under development: Not open for comment. Do not cite|
|Ahr mediated early stage mortality via cardiovascular toxicity||KeyEvent||Prarthana Shankar (send email)||Under development: Not open for comment. Do not cite|
Key Event Description
Descriptions of the KE comes from two studies that discovered and described slincR in zebrafish (Garcia et al., 2017; Garcia et al., 2018).
The sox9b long intergenic non-coding RNA or slincR is a novel long non-coding RNA (lncRNA) that was recently discovered in developing zebrafish
slincR gene expression is dependent on Aryl hydrocarbon receptor (Ahr) activation, with slincR induced up to ~log2FC=5 in whole-animal zebrafish exposed to the potent Ahr ligand, TCDD. This induction takes place only in the presence of a functional Ahr protein. SlincR is also induced by multiple other Ahr ligands.
slincR is located approximately 40,000 bp upstream and antisense of the sox9b gene locus in zebrafish. sox9b is one of the most reduced transcripts in the jaw when zebrafish are exposed to TCDD (Xiong et al., 2008), and is one of two zebrafish paralogs of sox9, a critical transcription factor that has been implicated in several processes including chondrogenesis and cardiac development, in addition to skeletal development, male gonad genesis, and cancer progression (Panda et al., 2021; Lefebvre et al., 2017).
slincR was found to be enriched in the 5'UTR of the sox9b gene, suggesting possible interactions between slincR and sox9b. A slincR morpholino experiment demonstrated that slincR is required for sox9b repression.
Morpholino knockdown of slincR showed slincR's ability to regulate cartilage development, and play a role in TCDD-induced hemorrhaging, both via whole-animal transcriptomics and phenotypic analyses.
How It Is Measured or Detected
slincR gene expression can be measured by quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and has been measured in embryonic zebrafish at 48 and 96 hours post fertilization (hpf) (Garcia et al., 2017).
slincR tissue localization of expression can be measured by in situ hybridization and has been measured in embryonic zebrafish at 24, 36, 48, 60, and 72 hpf (Garcia et al., 2017).
slincR molecular localization can be measured by capture hybridization analysis of RNA targets (CHART) and was measured in 48 hpf zebrafish embryos (Garcia et al., 2018).
Domain of Applicability
- slincR was discovered and characterized in developing zebrafish (Garcia et al., 2017; Garcia et al., 2018).
- Additionally, putative mammalian orthologs have also been identified using the slncky Evolution Browser (Garcia et al., 2018). The mouse ortholog was identified from an unpublished RNA sequencing dataset from male and female mouse urogenital epithelial tissue exposed to TCDD using a combination of proximity to the sox9 locus and TCDD-induced gene expression. Only one lncRNA (2610035D17Rik) matched the criteria. The human ortholog (LINC00673) of the mouse lncRNA was identified using slncky. Expression of both the mouse and human lncRNA orthologs from NCBI were consistent with zebrafish slincR expression.
Garcia GR, Goodale BC, Wiley MW, La Du JK, Hendrix DA, Tanguay RL. 2017. In vivo characterization of an ahr-dependent long noncoding rna required for proper sox9b expression. Mol Pharmacol. 91(6):609-619.
Garcia GR, Shankar P, Dunham CL, Garcia A, La Du JK, Truong L, Tilton SC, Tanguay RL. 2018. Signaling events downstream of ahr activation that contribute to toxic responses: The functional role of an ahr-dependent long noncoding rna (slincr) using the zebrafish model. Environ Health Perspect. 126(11):117002.
Lefebvre V, Dvir-Ginzberg M. 2017. Sox9 and the many facets of its regulation in the chondrocyte lineage. Connect Tissue Res. 58(1):2-14.
Panda M, Tripathi SK, Biswal BK. 2021. Sox9: An emerging driving factor from cancer progression to drug resistance. Biochim Biophys Acta Rev Cancer. 1875(2):188517.
Xiong KM, Peterson RE, Heideman W. 2008. Aryl hydrocarbon receptor-mediated down-regulation of sox9b causes jaw malformation in zebrafish embryos. Mol Pharmacol. 74(6):1544-1553.