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J. Biol. Chem., Vol. 283, Issue 7, 4051-4060, February 15, 2008

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Genome-wide H3K9 Histone Acetylation Profiles Are Altered in Benzopyrene-treated MCF7 Breast Cancer Cells^*

Bekim Sadikovic¹, Joseph Andrews², David Carter^¶||, John Robinson^¶||, and David I. Rodenhiser^¶3

From the London Regional Cancer Program, London Health Sciences Centre, ^¶EpiGenWestern Research Group of the Children's Health Research Institute, ^||Robarts Research Institute, and the Departments of Biochemistry, Oncology, and Paediatrics, University of Western Ontario, London, Ontario N6A 4L6, Canada

Current toxicogenomic approaches generate transcriptional profiles that can identify functional gene expression signatures of environmental toxicants. However, the intricate processes governing transcription are overlaid with a complex set of molecular instructions involving epigenetic modifications. These commands regulate both gene expression and chromatin organization through coordinated sets of histone modifications and heritable DNA methylation patterns. Although the effects of specific environmental toxicants on gene expression are the subject of much study, the epigenetic effects of such compounds are poorly understood. Here we have used human promoter tiling arrays along with chromatin immunoprecipitation to identify changes in histone acetylation profiles because of chemical exposure. Chromatin from cells exposed to the polyaromatic hydrocarbon benzo(a)pyrene was immunoprecipitated with antibodies against acetylated histones. Affymetrix promoter tiling microarrays were probed to generate epigenomic profiles of hypo- and hyperacetylated chromatin localized to gene promoter regions. Statistical analyses, data mining, and expression studies revealed that treated cells possessed differentially acetylated gene promoter regions and gene-specific expression changes. This chromatin immunoprecipitation-on-chip approach permits genome-wide profiling of histone acetylation patterns that can identify chromatin-related signatures of environmental toxicants and potentially determine the molecular pathways these changes target. This approach also has potential applications for profiling histone modifications and DNA methylation changes during embryonic development, in cancer biology, and in the development and assessment of cancer therapeutics.

Received for publication, September 7, 2007 , and in revised form, December 5, 2007.

^* This work was supported in part by the London Regional Cancer Program Small Grants Competition and the Lawson Health Research Institute Internal Research Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3 and Tables 1–5.

¹ Recipient of a studentship from the Canadian Institutes of Health Research Strategic Training Program in Cancer Research and Technology Transfer.

² Supported by Grant 016506 from the Canadian Breast Cancer Research Alliance, with special funding support from the Canadian Breast Cancer Foundation and the Cancer Research Society.

³ To whom correspondence should be addressed: A4-134 Victoria Research Laboratories, London Health Sciences Centre, 790 Commissioners Rd. East, London, Ontario N6A 4L6, Canada. Fax: 519-685-8616; E-mail: drodenhi{at}uwo.ca.

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