title: Xenobiotics and loss of cell adhesion drive distinct transcriptional outcomes by aryl hydrocarbon receptor signaling.
abstract: The aryl hydrocarbon receptor (AhR) is a signal-regulated transcription factor, which is canonically activated by the direct binding of xenobiotics. In addition, switching cells from adherent to suspension culture also activates the AhR, representing a nonxenobiotic, physiological activation of AhR signaling. Here, we show that the AhR is recruited to target gene enhancers in both ligand [isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439)]-treated and suspension cells, suggesting a common mechanism of target gene induction between these two routes of AhR activation. However, gene expression profiles critically differ between xenobiotic- and suspension-activated AhR signaling. Por and Cldnd1 were regulated predominantly by ligand treatments, whereas, in contrast, ApoER2 and Ganc were regulated predominantly by the suspension condition. Classic xenobiotic-metabolizing AhR targets such as Cyp1a1, Cyp1b1, and Nqo1 were regulated by both ligand and suspension conditions. Temporal expression patterns of AhR target genes were also found to vary, with examples of transient activation, transient repression, or sustained alterations in expression. Furthermore, sequence analysis coupled with chromatin immunoprecipitation assays and reporter gene analysis identified a functional xenobiotic response element (XRE) in the intron 1 of the mouse Tiparp gene, which was also bound by hypoxia-inducible factor-1α during hypoxia and features a concatemer of four XRE cores (GCGTG). Our data suggest that this XRE concatemer site concurrently regulates the expression of both the Tiparp gene and its cis antisense noncoding RNA after ligand- or suspension-induced AhR activation. This work provides novel insights into how AhR signaling drives different transcriptional programs via the ligand versus suspension modes of activation.
authors.affiliation: School of Molecular and Biomedical Science (Biochemistry) and Australian Research Council Special Research Centre for the Molecular Genetics of Development, the University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Nan
authors.initials: N
authors.lastname: Hao
authors.forename: Kian Leong
authors.initials: KL
authors.lastname: Lee
authors.forename: Sebastian G B
authors.initials: SG
authors.lastname: Furness
authors.forename: Cecilia
authors.initials: C
authors.lastname: Bosdotter
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Murray L
authors.initials: ML
authors.lastname: Whitelaw
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D051379:Mice; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D059467:Transcriptome / Q000187:drug effects; D015262:Xenobiotics / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D015262:Xenobiotics; C098773:low density lipoprotein receptor-related protein 8