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Event: 2021

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, slincR expression

Short name
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Increase, slincR expression
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Biological Context

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Level of Biological Organization
Molecular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
eukaryotic cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
gene expression increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
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

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
Danio rerio Danio rerio High NCBI
Mus musculus Mus musculus Moderate NCBI
Homo sapiens Homo sapiens Moderate NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Embryo High
Development High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Unspecific High

Key Event Description

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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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help
  • 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.

References

List of the literature that was cited for this KE description. More help

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.