# Novel mechanism of aryl hydrocarbon receptor - mediated differential gene regulation

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2021 · $261,000

## Abstract

ABSTRACT
Aryl hydrocarbon Receptor (AhR), a mediator of xenobiotic toxicity, is known to function as a ligand-activated
transcription factor that binds to a xenobiotic response element (XRE, GCGTG motif) in association with its
heterodimerization partner, the AhR nuclear translocator (Arnt) protein. This proposal is built on our
observation that cinnabarinic acid (CA) mediated AhR-dependent induction of stanniocalcin 2 (stc2) attenuates
stress induced apoptosis and protects against liver injury both in vitro and in vivo. stc2 induction was achieved
in response to endogenous AhR agonist CA but not the classic exogenous AhR ligand 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD). Moreover, CA in contrast to TCDD, was unable to trigger prototypical AhR
target gene, cyp1a1 in hepatocytes and did not regulate xenobiotic metabolism. Therefore, stc2 and cyp1a1
genes exhibit mutually exclusive agonist-specific AhR-mediated transcriptional responsiveness with distinct
physiological consequences. As a part of my K01 research, we observed interaction of Metastasis-associated
protein 2 (MTA2), a known chromatin remodeling protein, with AhR exclusively upon CA treatment. AhR-MTA2
complex was recruited only to stc2, but not cyp1a1 promoter. In addition, CA treatment was able to exhibit
histone H4 lysine 5 acetylation specifically at stc2 promoter concomitant with AhR-MTA2 complex recruitment.
Our preliminary studies identified that chromatin architecture in addition to the primary DNA sequence
significantly contributes to the agonist-specific differential gene expression. Building on our preliminary studies
this proposal tests the hypothesis that CA-specific AhR-dependent epigenetic modifications and chromatin
restructuring dictates transcription regulation of stc2, which in turn is responsible for cytoprotection following
liver injury. Specific Aim 1 of this application will profile CA and TCDD specific epigenetic modifications as well
as will identify the readers-writers-erasers of the histone modifications recruited to the XRE bounds AhR-MTA2
complex. Specific Aim 2 will determine role of chromatin architecture in agonist specific stc2 regulation by
using CRISPR/Cas9 gene editing. Specific Aim 3 will interrogate mechanism by which CA-triggered stc2
protects against ethanol-induced apoptosis by identifying downstream cytoprotective pathway components
activated by stc2. Therefore, the objective of this application is to decode CA-specific AhR-mediated
transcription regulation of stc2 and decipher its cytoprotective function. Given stc2’s involvement in
cytoprotection against liver injury, understanding its CA-specific regulation may serve as a key to developing
future molecular therapeutics targeting hepatic diseases.

## Key facts

- **NIH application ID:** 10150005
- **Project number:** 5R01DK122028-04
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Aditya D Joshi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $261,000
- **Award type:** 5
- **Project period:** 2019-07-12 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10150005

## Citation

> US National Institutes of Health, RePORTER application 10150005, Novel mechanism of aryl hydrocarbon receptor - mediated differential gene regulation (5R01DK122028-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10150005. Licensed CC0.

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