title: Cross-species transcriptomic analysis elucidates constitutive aryl hydrocarbon receptor activity.
abstract: BACKGROUND
  Research 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  These findings, though preliminary, present a platform for further evaluating the role of the AHR in regulation of constitutive mRNA levels and physiologic function.
authors.forename: Ren X
authors.initials: RX
authors.lastname: Sun
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Chong
authors.forename: Trent T
authors.initials: TT
authors.lastname: Simmons
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Houlahan
authors.forename: Stephenie D
authors.initials: SD
authors.lastname: Prokopec
authors.forename: John D
authors.initials: JD
authors.lastname: Watson
authors.forename: Ivy D
authors.initials: ID
authors.lastname: Moffat
authors.forename: Sanna
authors.initials: S
authors.lastname: Lensu
authors.forename: Jere
authors.initials: J
authors.lastname: Lindén
authors.forename: Christine
authors.initials: C
authors.lastname: P'ng
authors.forename: Allan B
authors.initials: AB
authors.lastname: Okey
authors.forename: Raimo
authors.initials: R
authors.lastname: Pohjanvirta
authors.affiliation: Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Canada. Paul.Boutros@oicr.on.ca.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D009928:Organ Specificity; D011485:Protein Binding; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity; D059467:Transcriptome
chemical_list: D018336:Receptors, Aryl Hydrocarbon