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Maureen A. Sartor,^1,*,** Michael Schnekenburger,^2,*,# Jennifer L. Marlowe,^2,## John F. Reichard,² Ying Wang,² Yunxia Fan,² Ci Ma,² Saikumar Karyala,² Danielle Halbleib,² Xiangdong Liu,¹ Mario Medvedovic,¹ and Alvaro Puga²

¹Laboratory for Statistical Genomics and Systems Biology, and ²Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

Abstract
Background: The vertebrate aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular responses to environmental polycyclic and halogenated compounds. The naive receptor is believed to reside in an inactive cytosolic complex that translocates to the nucleus and induces transcription of xenobiotic detoxification genes after activation by ligand.

Objectives: We conducted an integrative genomewide analysis of AHR gene targets in mouse hepatoma cells and determined whether AHR regulatory functions may take place in the absence of an exogenous ligand.

Methods: The network of AHR-binding targets in the mouse genome was mapped through a multipronged approach involving chromatin immunoprecipitation/chip and global gene expression signatures. The findings were integrated into a prior functional knowledge base from Gene Ontology, interaction networks, Kyoto Encyclopedia of Genes and Genomes pathways, sequence motif analysis, and literature molecular concepts.

Results: We found the naive receptor in unstimulated cells bound to an extensive array of gene clusters with functions in regulation of gene expression, differentiation, and pattern specification, connecting multiple morphogenetic and developmental programs. Activation by the ligand displaced the receptor from some of these targets toward sites in the promoters of xenobiotic metabolism genes.

Conclusions: The vertebrate AHR appears to possess unsuspected regulatory functions that may be potential targets of environmental injury.

Key words: Ah receptor, ChIP-on-chip, gene–environment interactions, gene regulation, gene target networks. Environ Health Perspect 117:1139–1146 (2009) . doi:10.1289/ehp.0800485 available via http://dx.doi.org/ [Online 24 March 2009]

Address correspondence to A. Puga, Department of Environmental Health, University of Cincinnati College of Medicine, 3223 Eden Ave., Cincinnati, OH 45220 USA. Telephone: (513) 558-0916. Fax: (513) 558-0925. E-mail: Alvaro.Puga@UC.EDU

*These authors contributed equally to this work.

**Current address: Center for Computational Medicine and Biology, University of Michigan, Ann Arbor, MI, USA.

#Current address: Laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Hôpital Kirchberg, Luxembourg.

^##Current address: Novartis Institutes for Biomedical Research, Cambridge, MA, USA.

Supplemental Material is available online at http://www.ehponline.org/docs/2009/0800485/suppl.pdf

We thank Y. Xia, D. Nebert, S. Khan, P. Stambrook, and G. Omenn for a critical reading of the manuscript and for many helpful suggestions.

The genomewide chromatin immunoprecipitation data have been submitted to the Gene Expression Omnibus database with access URL http://www.ncbi.nlm.nih.gov/projects/geo/query/acc.cgi?acc=GSE11850. The global expression profile data has the access URL http://www.ncbi.nlm.nih.gov/projects/geo/query/acc.cgi?acc=GSE11796.

This research was supported by grants from National Institute of Environmental Health Sciences (NIEHS) to A.P. (R01 ES06273 and R01 ES10807) , NIEHS Center for Environmental Genetics to A.P. and M.M. (P30 ES06096) , and National Institute of Health to M.M. (R01 HG003749 and R21 LM009662) . J.F.R. was supported by NIEHS T32 ES07250, Environmental Carcinogenesis and Mutagenesis Training Grant.

The authors declare they have no competing financial interests.

Received 13 December 2008 ; accepted 24 March 2009.