# Defining the developmental and toxicological roles of the AHR-regulated Sox9 lncRNA in zebrafish

> **NIH NIH R01** · OREGON STATE UNIVERSITY · 2020 · $397,610

## Abstract

PROJECT SUMMARY/ABSTRACT
The aryl hydrocarbon receptor (AHR) is required for proper vertebrate development and is activated by a
diverse group of chemicals including common pollutants such as chlorinated dioxins, polycyclic aromatic
hydrocarbons (PAHs), and coplanar polychlorinated biphenyls. In vertebrates, exposure to chemicals that
activate the AHR during early life stages is associated with adverse birth outcomes and impaired
neurodevelopment; however, the signaling events downstream of AHR and the genes contributing to toxic
responses remain largely unknown. Our long-term goal is to decipher conserved AHR-mediated biological
responses via discovery and validation of the causal genes and signaling mechanisms involved in AHR
regulated developmental and toxicological processes. We previously identified a novel and phylogenetically
conserved long non-coding RNA (slincR) that is induced by multiple environmentally relevant AHR
ligands. SlincR is required for the AHR-induced repression of sox9b, a master regulator of cartilage
development, and plays a causal role in AHR-mediated hemorrhaging and cartilage defects. The objective
of this proposal is to identify the developmental and toxicological roles of the AHR-regulated lncRNA,
slincR, in zebrafish. The central hypothesis is that slincR is a critical AHR-downstream signaling factor
potentiating adverse developmental responses to diverse xenobiotic chemicals. Our rationale is that
understanding how slincR functions and what other factors it interacts with will deepen the understanding
of AHR-signaling with the potential to uncover human therapeutic targets for AHR-related disease. We
will test our hypothesis by performing loss- and gain-of-function studies to determine the in vivo role of
slincR in AHR regulated developmental and toxicological processes (Aim 1). To understand the slincR
structure-function relationship with AHR signaling, we will perform structure-mapping experiments and
identify the slincR interacting proteins and genome-wide targets (Aim 2). We will use computational
approaches to integrate the findings of Aims 1 & 2 into the construction of an AHR gene regulatory network,
establishing a systems-level understanding of slincR in AHR-regulated biological processes (Aim 3). This
contribution is significant as it will unravel the functional impact of AHR activation on slincR expression
and provide a new paradigm for understanding AHR-dependent cellular responses. The proposed research
is innovative as we employ cutting-edge technologies new to the field of environmental health sciences.
Our proposal will also help to describe a novel adverse outcome pathway (AOP) for dioxin-like AHR ligands
that incorporate multiple biological levels including molecular structure, molecular interactions, co-
regulated genes, signaling networks, tissue development and whole animal phenotypes. These studies will
serve as a template for the systematic functional characterization of lncRNA potentiating b...

## Key facts

- **NIH application ID:** 9852443
- **Project number:** 5R01ES030017-02
- **Recipient organization:** OREGON STATE UNIVERSITY
- **Principal Investigator:** Robyn L Tanguay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,610
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852443

## Citation

> US National Institutes of Health, RePORTER application 9852443, Defining the developmental and toxicological roles of the AHR-regulated Sox9 lncRNA in zebrafish (5R01ES030017-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852443. Licensed CC0.

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