Novel Roles of the Aryl Hydrocarbon Receptor in Normal Physiology and Epigenetic Reprogramming

The Aryl hydrocarbon Receptor (AhR) is a ubiquitously expressed, evolutionarily conserved, ligand activated, cytosolic transcription factor belonging to the basic Helix-loop-helix Per-ARNT-Sim superfamily of proteins. AhR has classically been associated with environmental toxicology owing to the fact it mediates the toxic effects of halogenated aromatic hydrocarbons and environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD exposure in laboratory animals is linked to carcinogenicity, hepatic steatosis, and a lethal wasting syndrome. In recent years, AhR knockout and antagonism have been reported to confer resistance to western diet induced obesity as well as reversing diet induced obesity. Together, these observations suggest a direct role for AhR regulating normal metabolic homeostasis and implicate AhR as a potential therapeutic target for obesity. However, much of the foundational knowledge of AhR biology is based on the use of exogenous, toxic AhR agonists. Through the use of a hepatocyte specific, inducible AhR knockout mouse model, the studies presented in this dissertation seek to address the gap in knowledge of the normal, physiologic functions of AhR in the absence of man-made toxicants. In addition to revealing the physiologic functions of AhR, this work also investigates a non-canonical AhR signaling pathway mediated by a novel protein complex consisting of AhR, Kruppel-like factor 6 (KLF6) and carbamoyl phosphate synthetase 1 (CPS1). This complex binds a unique DNA motif termed the Non-Consensus Xenobiotic Response Element (NC-XRE). CPS recruitment results in homocitrullination of linker histone H1 lysine 34 (H1K34hcit). Homocitrullination, a novel epigenetic mark, was observed only in response to exogenous AhR agonists and is absent upon treatment with endogenous AhR ligands such as cinnabarinic acid. Results presented here demonstrate AhR-CPS1 dependent H1K34hcit is associated specifically with Pai-1 and Padi2 promoters and is required for transcriptional regulation. We posit that H1K34hcit is responsible for increasing mobility of histone H1, altering the local chromatin structure, thereby favoring transcription of NC-XRE containing genes. This represents a novel paradigm for AhR in the epigenetic regulation of gene expression. The studies presented in this dissertation shed light on both the subtle, physiologic activity of AhR and the AhR mediated epigenetics of TCDD toxicity.

Name thesis:degree_name

Cell Biology (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2022

Author dc:creator

• Wright, Eric John

• Biology, Cell
• Biology, Genetics
• Biology, Molecular

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12616

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12616