PT  - JOURNAL ARTICLE
AU  - Nikhil Y Patil
AU  - Hui Tang
AU  - Iulia Rus
AU  - Kangling Zhang
AU  - Aditya D Joshi
TI  - Decoding cinnabarinic acid specific stanniocalcin 2 induction by aryl hydrocarbon receptor
AID  - 10.1124/molpharm.121.000376
DP  - 2021 Jan 01
TA  - Molecular Pharmacology
PG  - MOLPHARM-AR-2021-000376
4099  - http://molpharm.aspetjournals.org/content/early/2021/11/11/molpharm.121.000376.short
4100  - http://molpharm.aspetjournals.org/content/early/2021/11/11/molpharm.121.000376.full
AB  - Aryl hydrocarbon Receptor (AhR) is a ligand mediated transcription factor known for regulating response to xenobiotics, including prototypical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the activation of cytochrome P450 1A1 (encoded by cyp1a1) expression. Upon ligand-binding AhR translocate to nucleus, interacts with AhR nuclear translocator (Arnt) and bind to xenobiotic response element(s) (GCGTG, XREs) present in the promoter region of AhR regulated genes. Recently, we identified a novel tryptophan catabolite, cinnabarinic acid (CA) as an endogenous AhR agonist capable of activating expression of AhR target gene, stanniocalcin 2 (stc2). The CA-driven stc2 induction bestowed cytoprotection against hepatotoxicity in an AhR-dependent manner. Interestingly, only CA, but not TCDD was able to induce stc2 expression in liver and CA was unable to upregulate the TCDD responsive cyp1a1 gene. In this report, we identified CA-specific histone H4 K5 acetylation and H3 K79 methylation at AhR-bound stc2 promoter. Moreover, histone H4 K5 acetylation writer, Atf2 and H3 K79 methylation writer, Dot1l were interacting with AhR-complex at stc2 promoter exclusively in response to CA treatment concurrent with the histone epigenetic marks. Suppressing Atf2 and Dot1l expression using RNA interference confirmed their role in stc2 expression. CRISPR/Cas9 assisted replacement of cyp1a1 promoter XREs with stc2 promoter XREs resulted in CA-dependent induction of cyp1a1 underlining fundamental role of quaternary structure of XRE sequence in agonist-specific gene regulation. In conclusion, CA-driven recruitment of specific chromatin regulators to AhR complex and resulting histone epigenetic modifications may serve as a molecular basis for agonist specific stc2 regulation by AhR. Significance Statement Results reported here provide a mechanistic explanation for the agonist-specific differential gene regulation by identifying interaction of AhR with specific chromatin regulators concomitant with unique histone epigenetic marks. This study also demonstrated that the agonist-specific target gene expression can be transferred with the gene-specific promoter XRE sequence in the context of chromatin architecture.