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Decoding Cinnabarinic Acid–Specific Stanniocalcin 2 Induction by Aryl Hydrocarbon Receptor
- Source :
- Mol Pharmacol
- Publication Year :
- 2021
- Publisher :
- American Society for Pharmacology & Experimental Therapeutics (ASPET), 2021.
-
Abstract
- 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 CYP1A1 expression. Upon ligand-binding, AhR translocates to the nucleus, interacts with the AhR nuclear translocator, and binds to xenobiotic response elements (XREs; GCGTG) 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 lysine 5 acetylation and H3 lysine 79 methylation at the AhR-bound stc2 promoter. Moreover, histone H4 lysine 5 acetylation writer, activating transcription factor 2 (Atf2), and H3 lysine 79 methylation writer, disruptor of telomeric silencing 1-like histone lysine methyltransferase (Dot1l), were interacting with the AhR complex at the 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-encompassing XREs with stc2 promoter XREs resulted in CA-dependent induction of cyp1a1, underlining a fundamental role of quaternary structure of XRE sequence in agonist-specific gene regulation. In conclusion, CA-driven recruitment of specific chromatin regulators to the 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 aryl hydrogen receptor 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 xenobiotic response element-sequence in the context of chromatin architecture.
- Subjects :
- Aryl hydrocarbon receptor nuclear translocator
Response element
Cell Line
Histone H4
Mice
Oxazines
Basic Helix-Loop-Helix Transcription Factors
Animals
Glycoproteins
Pharmacology
Regulation of gene expression
biology
Chemistry
Articles
DOT1L
respiratory system
Aryl hydrocarbon receptor
Chromatin
Cell biology
Mice, Inbred C57BL
Histone
Liver
Receptors, Aryl Hydrocarbon
biology.protein
Intercellular Signaling Peptides and Proteins
Molecular Medicine
Female
Subjects
Details
- ISSN :
- 15210111 and 0026895X
- Volume :
- 101
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmacology
- Accession number :
- edsair.doi.dedup.....e9fdc6dd8c4244c3ea9635f2a7525e2f