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Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor.

ABSTRACT: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that binds DNA and regulates genes in response to halogenated and polycyclic aromatic hydrocarbons. AHR also regulates the development and function of the liver and the immune system. In the canonical pathway, AHR binds a consensus DNA sequence, termed the xenobiotic response element (XRE), recruits protein coregulators, and regulates target gene expression. Emerging evidence suggests that AHR may regulate gene expression via an additional pathway, by binding to a non-consensus DNA sequence termed the non-consensus XRE (NC-XRE). The prevalence of NC-XRE motifs in the genome is not known. Studies using chromatin immunoprecipitation and reporter genes provide indirect evidence of AHR-NC-XRE interactions, but direct evidence for an AHR-NCXRE interaction that regulates transcription in a natural genomic context is lacking. Here, we analyzed AHR binding to NC-XRE DNA on a genome-wide scale in mouse liver. We integrated ChIP-seq and RNA-seq data and identified putative AHR target genes with NC-XRE motifs in regulatory regions. We also performed functional genomics at a single locus, the mouse Serpine1 gene. Deleting NC-XRE motifs from the Serpine1 promoter reduced the upregulation of Serpine1 by TCDD, an AHR ligand. We conclude that AHR upregulates Serpine1 via NC-XRE DNA. NC-XRE motifs are prevalent throughout regions of the genome where AHR binds. Taken together, our results suggest that AHR regulates genes via NC-XRE motifs. Our results will also improve our ability to identify AHR target genes and their physiologic relevance.

SUBMITTER: Patel TD

PROVIDER: S-EPMC10187216 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor.

Shahriar Shayan S Patel Tajhal D TD Nakka Manjula M Grimm Sandra L SL Coarfa Cristian C Gorelick Daniel A DA

bioRxiv : the preprint server for biology 20250522

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that is activated by environmental toxicants, like halogenated and polycyclic aromatic hydrocarbons, and then binds to DNA and regulates gene expression. AHR is involved in various physiological processes, including liver and immune system function, cell cycle regulation, oncogenesis, and metabolism. In the canonical pathway, AHR binds to a consensus DNA sequence (GCGTC), termed the xenobiotic response element (XRE), ...[more]

PMID: 37205451

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Project description:Background & aimsIn autoimmune hepatitis (AIH), the imbalance between regulatory T cells (Tregs) and T-helper type 17 (Th17) cells has been linked to low levels of CD39, an ectoenzyme that hydrolyses ATP, ultimately generating immunosuppressive adenosine. Upregulation of CD39 results from activation of aryl hydrocarbon receptor (AHR), which mediates toxin responses to modulate T-cell immunity. In this study, we investigated whether altered AHR signalling underlies defective CD39 expression and function in AIH Tregs and Th17 cells, therefore contributing to regulatory/effector cell imbalance.MethodsTregs and Th17 cells, obtained from the peripheral blood of 49 patients with AIH and 21 healthy individuals (HI), were tested for response to endogenous and exogenous AHR ligands.ResultsWhen compared to those of HI, AIH-derived Tregs and Th17 cells displayed impaired responses to AHR activation, reflected by impaired upregulation of CD39, delayed increase in ectoenzymatic activity, and defective Treg suppressive function. These impairments resulted, at least in part, from heightened levels of AHRR and Erα in Tregs and high HIF-1α in Th17 cells, and were reverted upon molecular blockade. Importantly, in AIH-derived Tregs, the binding affinity of AHR was higher for Erα than ARNT.ConclusionsIn AIH, high levels of AHRR and HIF-1α inhibit AHR signalling in Tregs and Th17 cells. AHR non-canonical binding to Erα further amplifies the lack of effective CD39 upregulation. Blockade of these inhibitory and/or non-canonical activation pathways represents a potential therapeutic approach to restore CD39 and immunohomeostasis in AIH.Lay summaryIn patients with autoimmune hepatitis, the imbalance between regulatory T cells and T helper type-17 cells is linked to dysfunction of the aryl hydrocarbon receptor pathway, resulting from aberrant inhibition or non-canonical activation. These alterations impair Treg- and Th17 cell-induced upregulation of CD39, an ectoenzyme key to immunoregulation. Blockade of excessive inhibition or non-canonical activation of the aryl hydrocarbon receptor pathway might represent a novel therapeutic strategy to control inflammation while restoring immune balance in autoimmune hepatitis.

Dataset Information

Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor.

Publications

Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor.

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