Abstract
BackgroundResearch on the aryl hydrocarbon receptor (AHR) has largely focused on variations in toxic outcomes resulting from its activation by halogenated aromatic hydrocarbons. But the AHR also plays key roles in regulating pathways critical for development, and after decades of research the mechanisms underlying physiological regulation by the AHR remain poorly characterized. Previous studies identified several core genes that respond to xenobiotic AHR ligands across a broad range of species and tissues. However, only limited inferences have been made regarding its role in regulating constitutive gene activity, i.e. in the absence of exogenous ligands. To address this, we profiled transcriptomic variations between AHR-active and AHR-less-active animals in the absence of an exogenous agonist across five tissues, three of which came from rats (hypothalamus, white adipose and liver) and two of which came from mice (kidney and liver). Because AHR status alone has been shown sufficient to alter transcriptomic responses, we reason that by contrasting profiles amongst AHR-variant animals, we may elucidate effects of the AHR on constitutive mRNA abundances.ResultsWe found significantly more overlap in constitutive mRNA abundances amongst tissues within the same species than from tissues between species and identified 13 genes (Agt, Car3, Creg1, Ctsc, E2f6, Enpp1, Gatm, Gstm4, Kcnj8, Me1, Pdk1, Slc35a3, and Sqrdl) that are affected by AHR-status in four of five tissues. One gene, Creg1, was significantly up-regulated in all AHR-less-active animals. We also find greater overlap between tissues at the pathway level than at the gene level, suggesting coherency to the AHR signalling response within these processes. Analysis of regulatory motifs suggests that the AHR mostly mediates transcriptional regulation via direct binding to response elements.ConclusionsThese findings, though preliminary, present a platform for further evaluating the role of the AHR in regulation of constitutive mRNA levels and physiologic function.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1053) contains supplementary material, which is available to authorized users.
Highlights
Research on the aryl hydrocarbon receptor (AHR) has largely focused on variations in toxic outcomes resulting from its activation by halogenated aromatic hydrocarbons
Since TCDD toxicity is mediated via the classical AHR activation pathway and the adipose and hypothalamic tissues are major sites within the body for energy storage and feeding regulation, these tissues were selected as proxies to measure constitutive AHR effects [61]
We performed withinexperiment linear modelling and imposed a significance selection criterion (q < 0.05); this revealed a range of 231 genes to 1,443 genes whose mRNA levels were differentially-abundant within experiments (Figure 1A). mRNA levels for these genes were dependent on AHR-status across multiple species and tissues (Figure 1B)
Summary
Research on the aryl hydrocarbon receptor (AHR) has largely focused on variations in toxic outcomes resulting from its activation by halogenated aromatic hydrocarbons. The aryl hydrocarbon receptor (AHR) is an evolutionarilyconserved, ligand-activated transcription factor and a member of the basic helix-loop-helix/PER-ARNT-SIM family [1] Proteins within this family participate in signalling and metabolic pathways important for the regulation of circadian rhythm, development and responses to and participation in molecular cross-talk [10,11,12,13,14,15]. The classical activation pathway is initiated by ligand-binding, and followed by receptor hetero-dimerization, entry into the nucleus and interactions with regulatory regions of target genes to alter their transcript abundance [23] By virtue of this ligand imperative, it is probable that the AHR relies on endogenous activators to carry out its developmental responsibilities. There are numerous candidate endogenous AHR ligands, our understanding of their physiologic roles remains incomplete
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