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Molecular and Cellular Biology, October 2007, p. 7089-7101, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00838-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Chromium Cross-Links Histone Deacetylase 1-DNA Methyltransferase 1 Complexes to Chromatin, Inhibiting Histone-Remodeling Marks Critical for Transcriptional Activation{triangledown}

Michael Schnekenburger, Glenn Talaska, and Alvaro Puga*

Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, Ohio 45267-0056

Received 12 May 2007/ Returned for modification 25 June 2007/ Accepted 26 July 2007

Transcriptional regulation of gene expression requires posttranslational modification of histone proteins, which, in concert with chromatin-remodeling factors, modulate chromatin structure. Exposure to environmental agents may interfere with specific histone modifications and derail normal patterns of gene expression. To test this hypothesis, we coexposed cells to binary mixtures of benzo[a]pyrene (B[a]P), an environmental procarcinogen that activates Cyp1a1 transcriptional responses mediated by the aryl hydrocarbon receptor (AHR), and chromium, a carcinogenic heavy metal that represses B[a]P-inducible AHR-mediated gene expression. We show that chromium cross-links histone deacetylase 1-DNA methyltransferase 1 (HDAC1-DNMT1) complexes to Cyp1a1 promoter chromatin and inhibits histone marks induced by AHR-mediated gene transactivation, including phosphorylation of histone H3 Ser-10, trimethylation of H3 Lys-4, and various acetylation marks in histones H3 and H4. These changes inhibit RNA polymerase II recruitment without affecting the kinetics of AHR DNA binding. HDAC1 and DNMT1 inhibitors or depletion of HDAC1 or DNMT1 with siRNAs blocks chromium-induced transcriptional repression by decreasing the interaction of these proteins with the Cyp1a1 promoter and allowing histone acetylation to proceed. By inhibiting Cyp1a1 expression, chromium stimulates the formation of B[a]P DNA adducts. Epigenetic modification of gene expression patterns may be a key element of the developmental and carcinogenic outcomes of exposure to chromium and to other environmental agents.

* Corresponding author. Mailing address: Department of Environmental Health, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056. Phone: (513) 558-0916. Fax: (513) 558-0925. E-mail: Alvaro.Puga{at}UC.EDU

{triangledown} Published ahead of print on 6 August 2007.

Molecular and Cellular Biology, October 2007, p. 7089-7101, Vol. 27, No. 20
0270-7306/07/$08.00+0     doi:10.1128/MCB.00838-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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