Chromium Inhibits Transcription from Polycyclic Aromatic Hydrocarbon-inducible Promoters by Blocking the Release of Histone Deacetylase and Preventing the Binding of p300 to Chromatin

Abstract

Co-contamination with complex mixtures of carcinogenic metals, such as chromium, and polycyclic aromatic hydrocarbons is a common environmental problem with multiple biological consequences. Chromium exposure alters inducible gene expression, forms chromium-DNA adducts and chromium-DNA cross-links, and disrupts transcriptional activator-co-activator complexes. We have shown previously that exposure of mouse hepatoma Hepa-1 cells to chromate inhibits the induction of the Cyp1a1 and Nqo1 genes by dioxin. Here we have tested the hypothesis that chromium blocks gene expression by interfering with the assembly of productive transcriptional complexes at the promoter of inducible genes. To this end, we have studied the effects of chromium on the expression of genes induced by benzo[a]pyrene (B[a]P), another aryl hydrocarbon receptor agonist, and characterized the disruption of Cyp1a1 transcriptional induction by chromium. Gene expression profiling by using high density microarray analysis revealed that the inhibitory effect of chromium on B[a]P-dependent gene induction was generalized, affecting the induction of over 50 different genes involved in a variety of signaling transduction pathways. The inhibitory effect of chromium on Cyp1a1 transcription was found to depend on the presence of promoter-proximal sequences and not on the cis-acting enhancer sequences that bind the aryl hydrocarbon receptor-aryl hydrocarbon receptor nuclear translocator complex. By using transient reporter assays and chromatin immunoprecipitation analyses, we found that chromium prevented the B[a]P-dependent release of HDAC-1 from Cyp1a1 chromatin and blocked p300 recruitment. These results provide a mechanistic explanation for the observation that chromium inhibits inducible but not constitutive gene expression. Co-contamination with complex mixtures of carcinogenic metals, such as chromium, and polycyclic aromatic hydrocarbons is a common environmental problem with multiple biological consequences. Chromium exposure alters inducible gene expression, forms chromium-DNA adducts and chromium-DNA cross-links, and disrupts transcriptional activator-co-activator complexes. We have shown previously that exposure of mouse hepatoma Hepa-1 cells to chromate inhibits the induction of the Cyp1a1 and Nqo1 genes by dioxin. Here we have tested the hypothesis that chromium blocks gene expression by interfering with the assembly of productive transcriptional complexes at the promoter of inducible genes. To this end, we have studied the effects of chromium on the expression of genes induced by benzo[a]pyrene (B[a]P), another aryl hydrocarbon receptor agonist, and characterized the disruption of Cyp1a1 transcriptional induction by chromium. Gene expression profiling by using high density microarray analysis revealed that the inhibitory effect of chromium on B[a]P-dependent gene induction was generalized, affecting the induction of over 50 different genes involved in a variety of signaling transduction pathways. The inhibitory effect of chromium on Cyp1a1 transcription was found to depend on the presence of promoter-proximal sequences and not on the cis-acting enhancer sequences that bind the aryl hydrocarbon receptor-aryl hydrocarbon receptor nuclear translocator complex. By using transient reporter assays and chromatin immunoprecipitation analyses, we found that chromium prevented the B[a]P-dependent release of HDAC-1 from Cyp1a1 chromatin and blocked p300 recruitment. These results provide a mechanistic explanation for the observation that chromium inhibits inducible but not constitutive gene expression. Environmental exposures to toxic or carcinogenic compounds rarely result from the presence of single, isolated toxicants. More often, the toxic agent is a complex mixture of chemical entities in numbers ranging from a few, such as may occur in occupational exposures, to several hundred, such as in cigarette smoke. Often, these mixtures include a combination of carcinogenic metals and polycyclic aromatic hydrocarbons, as for example those co-released from sources such as fossil fuel combustion or municipal waste incineration. Of these, chromium and B[a]P 1The abbreviations used are: B[a]Pbenzo[a]pyreneAHRaryl hydrocarbon receptorAHaryl hydrocarbonPBSphosphate-buffered salinePIPES1,4-piperazinediethanesulfonic acidARNTAh receptor nuclear translocatorCBPCREB-binding proteinCREBcAMP-response element-binding proteinChIPchromatin immunoprecipitationHAThistone acetyltransferaseHDAChistone deacetylaseHDACICP-MS, inductively coupled plasma mass spectrometrySRCsteroid receptor co-activatorTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycineCy3cytidine-3Cy5cytidine-5HSV-1herpes simplex virus, type 1TCDD2,3,7,8-tetrachlorodibenzo-p-dioxin. are among the top 20 hazardous substances in the Agency for Toxic Substances and Disease Registry/Environmental Protection Agency priority list (1Agency for Toxic Substances and Disease Registry Report (2002) CERCLA Priority List of Hazardous Substances, http://www.atsdr.cdc.gov/clist.htmlGoogle Scholar) and are found as co-contaminants in more than 25% of the National Priority List of Superfund sites (2United States Environmental Protection Agency (2003) National Priorities List, http://oaspub.epa.gov/oerrpage/basicqryGoogle Scholar). benzo[a]pyrene aryl hydrocarbon receptor aryl hydrocarbon phosphate-buffered saline 1,4-piperazinediethanesulfonic acid Ah receptor nuclear translocator CREB-binding protein cAMP-response element-binding protein chromatin immunoprecipitation histone acetyltransferase histone deacetylase ICP-MS, inductively coupled plasma mass spectrometry steroid receptor co-activator N-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine cytidine-3 cytidine-5 herpes simplex virus, type 1 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chromium has been known for over 100 years to be a human carcinogen (3Klein C.B. Chang L.W. Toxicology of Metals. CRC Press Inc., Boca Raton, FL1996: 205-219Google Scholar). Epidemiologically, the greatest risk of cancer from chromium exposure is associated with Cr(VI). Cr(VI) enters cells via the sulfate anion transporter system and is reduced to intermediate oxidation states, such as Cr(V) and Cr(IV), in the process of forming stable Cr(III) forms (4Wetterhahn K.E. Hamilton J.W. Aiyar J. Borges K.M. Floyd R. Biol. Trace Elem. Res. 1989; 21: 405-411Crossref PubMed Scopus (75) Google Scholar, 5Bagchi D. Stohs S.J. Downs B.W. Bagchi M. Preuss H.G. Toxicology. 2002; 180: 5-22Crossref PubMed Scopus (566) Google Scholar). Cr(III) is the most prevalent form of chromium in the environment and in biological tissues, but the vast majority of the evidence indicates that exposure to trivalent chromium does not induce tumors in animals (6International Agency for Research on Cancer Evaluation of the Carcinogenic Risk to Humans,49. IARC Press, Vol. , pp. , Lyon, France1990: 120-139Google Scholar). The available experimental evidence indicates that chromium exposure has little or no effect on constitutive gene expression but alters inducible gene expression, possibly due to the formation of chromium-DNA adducts, chromium-DNA cross-links, or to the disruption of transcriptional activator-coactivator complexes (3Klein C.B. Chang L.W. Toxicology of Metals. CRC Press Inc., Boca Raton, FL1996: 205-219Google Scholar, 7Alcedo J.A. Misra M. Hamilton J.W. Wetterhahn K.E. Carcinogenesis. 1994; 15: 1089-1092Crossref PubMed Scopus (27) Google Scholar, 8Hamilton J.W. Wetterhahn K.E. Mol. Carcinog. 1989; 2: 274-286Crossref PubMed Scopus (86) Google Scholar, 9Shumilla J.A. Broderick R.J. Wang Y. Barchowsky A. J. Biol. Chem. 1999; 274: 36207-36212Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). For example, chromium was found to block the expression of metal-inducible metallothionein or hormone-inducible phosphoenolpyruvate carboxykinase without affecting the expression of housekeeping genes, such as β-actin or albumin (4Wetterhahn K.E. Hamilton J.W. Aiyar J. Borges K.M. Floyd R. Biol. Trace Elem. Res. 1989; 21: 405-411Crossref PubMed Scopus (75) Google Scholar, 7Alcedo J.A. Misra M. Hamilton J.W. Wetterhahn K.E. Carcinogenesis. 1994; 15: 1089-1092Crossref PubMed Scopus (27) Google Scholar, 8Hamilton J.W. Wetterhahn K.E. Mol. Carcinog. 1989; 2: 274-286Crossref PubMed Scopus (86) Google Scholar, 10Wetterhahn K.E. Hamilton J.W. Sci. Total Environ. 1989; 86: 113-129Crossref PubMed Scopus (113) Google Scholar, 11McCaffrey J. Wolf C.M. Hamilton J.W. Mol. Carcinog. 1994; 10: 189-198Crossref PubMed Scopus (32) Google Scholar). These observations have led to the hypothesis that the chromatin structure of inducible promoters, perhaps by virtue of being more open, may offer a better target for chromium binding than the more closed chromatin of constitutive promoters (12Manning F.C. Xu J. Patierno Mol. Carcinog. PubMed Scopus Google Scholar). are found in nuclear J. F.C. Patierno Carcinogenesis. 1994; 15: PubMed Scopus Google and transcription that and or several of these may be for of from the of Cr(VI) to Cr(V) and of binding but not a in gene expression J. Y. PubMed Scopus Google Scholar, Hamilton J.W. Mol. Carcinog. 1999; PubMed Scopus Google Scholar, J. Y. Carcinogenesis. PubMed Scopus Google possibly chromium blocks the binding of the to with is for transcriptional J.A. Broderick R.J. Wang Y. Barchowsky A. J. Biol. Chem. 1999; 274: 36207-36212Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). These that the intermediate oxidation of chromium may be for effect on gene expression. The for this effect is to the process in the of affecting of transcription with transcriptional and chromatin more than the binding of the to from this have shown that exposure of mouse hepatoma Hepa-1 cells to chromate inhibits the induction of the Cyp1a1 and Nqo1 genes by A. A. Mol. Carcinog. PubMed Scopus Google Scholar). The is a transcription that forms with and to cis-acting enhancer in the of target genes, such as Cyp1a1 and to in chromatin structure and of gene transcription 1999; PubMed Scopus Google Scholar). These include the to the transcription of associated years several transcriptional the the chromatin and the have been shown to with complexes and a in A. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Y. J. PubMed Scopus Google Scholar, J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, Gene 1999; Google Scholar, Wang J. Mol. Biol. 2002; PubMed Scopus Google Scholar, D. 1999; PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar, J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). We have studied the effects of chromium on the expression of genes induced by another We have tested the hypothesis that of gene expression by chromium was not to Cyp1a1 or Nqo1 but that a of genes induced by We have tested the hypothesis that chromium blocked gene expression by interfering with the assembly of productive transcriptional complexes in the promoters of inducible genes. We that chromium the B[a]P-dependent release of HDAC-1 from the of p300 with the Cyp1a1 transcriptional complex and gene and hepatoma Hepa-1 Biol. PubMed Scopus Google Scholar) cells in with 100 and 100 at cells have been previously A. Mol. Biol. PubMed Scopus Google by stable Hepa-1 cells of a reporter the of the mouse Cyp1a1 gene promoter to to the promoter from to R. R. Full Text PDF PubMed Scopus Google Scholar) from the been chromate and and to as in to was in to B[a]P was to the cells in a of are in the and the and gene expression, we used the reporter A. Mol. Biol. PubMed Scopus Google the mouse Cyp1a1 gene promoter from to the co-activator p300 from human expression and and by and of For cells in at a density of and at using 50 of reporter of or and of with for in and was and the mixture was for The was for and the was to and cells to cells with and with 100 of reporter of 50 of used to of of and of using a for in transient using and was isolated using to the with to used for microarray To to for microarray analyses, using was by transcription of 20 of in a of 20 of and of at for 1 and the was by to for For of with mouse Cyp1a1 a of and of the mouse Cyp1a1 of was with and a of of the was used as was in the in a of of and mouse Cyp1a1 The mixtures to for and a at a at and a at of was to be the at a in at was in The shown the of experimental to cells with to the β-actin in the of and of of and by the of and are from 20 of using J. M. Y. PubMed Scopus Google Scholar). The was by and the was with cytidine-3 and cytidine-5 and of the may be found at The from mouse from the sequences from mouse genes, in a to The the and and in and to the microarray for high and and with at was in with to for the of of microarray in the was with and in was with the to from was of with as with and by the to genes different experimental was in for microarray from the of and and the and of as and and the and was by the of as a of Scholar). The the and the the gene expression for the by a of the to for the and of the from for the of analysis was for gene by the effects J. Biol. PubMed Scopus Google to the on the with the combination and with the 1 for and for is the is the effect of the is the effect of the and is the effect of the the as J. Biol. PubMed Scopus Google with effects to be and and effects to be of the expression different for the and was by for hypothesis was by A. D. Y. PubMed Scopus Google Scholar, Y. Y. J. R. Scholar). and using Inc., Chromium cells with and isolated or 1 of with and by in cells with and with of The was by at and the was on at and by high using of by J.A. J. A. PubMed Scopus Google Scholar). a anion was with a 50 at a of The was for chromium at using for different chromium for for Cr(III) with and for a of Total Chromium cells with chromate or for with and cells from the in and by at for in of and of to a of on in at for The and the at and as the and nuclear For with to a of and for in a for chromium by using the and to a chromium in For of as was used The chromate of was with for and with and as and in a from cells with or B[a]P for or with 50 chromium for to B[a]P with from cells with 50 chromium the and assays as A. A. Mol. Carcinog. PubMed Scopus Google Scholar) with the that and of used for for at For those in chromium was to the in was of to a of 1 the of the at for and the was of the and was as previously A. A. Mol. Carcinog. PubMed Scopus Google Scholar). was using a on by J. 2002; PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar) with Hepa-1 cells to in with or B[a]P for 1 or with 50 chromium for by no or with B[a]P for was by a at with to the to a of The was by to a of with cells from the and with in the and on for on in a using the 20 to in The and in and on for was on with of with a of the was For chromatin was for at with protein with albumin and Inc., The was among and on a at with of p300 and HDAC-1 was and for at to to bind to the The and with and with complexes from the with was by the at for To for of a known of was to the The with at for was with and with in the was and was in for the of the of the Cyp1a1 promoter was by of a of of the promoter was with the and to the enhancer to The promoter was with the and to in and to in a and using Chromium of available experimental evidence indicates that chromium exposure has little or no effect on constitutive gene expression but alters inducible gene expression, possibly due to the formation of chromium-DNA adducts, chromium-DNA cross-links, or to the disruption of transcriptional activator-coactivator complexes J.A. Misra M. Hamilton J.W. Wetterhahn K.E. Carcinogenesis. 1994; 15: 1089-1092Crossref PubMed Scopus (27) Google Scholar, 9Shumilla J.A. Broderick R.J. Wang Y. Barchowsky A. J. Biol. Chem. 1999; 274: 36207-36212Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 10Wetterhahn K.E. Hamilton J.W. Sci. Total Environ. 1989; 86: 113-129Crossref PubMed Scopus (113) Google Scholar). from this have shown that chromium the induction of Cyp1a1 and Nqo1 by the induction of and gene expression A. A. Mol. Carcinog. PubMed Scopus Google Scholar). To that this was not a effect of we the effects of chromium on gene by the Ah receptor using another as the to the hypothesis that the inhibitory effect of chromium was a affecting inducible genes and not to genes for we expression of Hepa-1 cells with B[a]P or with chromium using a high density microarray analysis More than 50 genes, Cyp1a1 and Nqo1 among by B[a]P and induction was by of chromium to B[a]P The inhibitory effect of chromium was the cells induced with B[a]P and chromium was not These are in with results from this the of of chromium was to of A. A. Mol. Carcinog. PubMed Scopus Google Scholar). The list of genes by chromium genes involved in a variety of signaling transduction such as transcription and in to genes involved in is that the inhibitory effect of chromium is generalized, affecting the of more than a genes by chromium in a of Cr(III) in the observations on the effects of chromium on of led to that chromium disrupts gene expression at of transcription A. A. Mol. Carcinog. PubMed Scopus Google Scholar). that the be that chromium the cells and be the We used a combination of high and to chromium and in Hepa-1 Chromium was Cr(VI) being reduced to Cr(III) in the By 1 of the chromium was found as Cr(VI) by 1 Cr(VI) was than By Cr(VI) was not Chromium was by of and of chromate or of chromium in and nuclear a and found chromate or the of chromium These that a of the chromium to the cells enters the as reduced Cr(III) or in the process of being reduced from Cr(VI) to and inhibitory effect on gene expression by with the transcriptional Chromium chromium blocks inducible gene expression at of more than at is to that nuclear chromium, as Cr(III) or as a block transcription at of or To this we used transcriptional We transcription of several genes in the presence or of chromium to cells to nuclear or with the the The transcription of and was induced by B[a]P to the transcription of used to transcription to the of was by 50 chromium, as Cr(VI) to the cells to B[a]P or to from cells These results that chromium blocks the transcription of inducible genes to a than the expression of the housekeeping used to the of Gene by Chromium at the of the of several such as and the by chromium of B[a]P-dependent gene expression induction not the the evidence of and nuclear that Cr(III) or a intermediate Cr(VI) and Cr(III) was to with of the transcriptional and block the effect in transcription we that chromium with the to assembly of the transcriptional complex on the Cyp1a1 promoter To this we used the cells that a reporter this expression is by the enhancer of the mouse Cyp1a1 gene promoter this the enhancer is to the promoter from the been these expression of and Cyp1a1 genes is induced by the of the Cyp1a1 promoter to the transcription with the promoter the of Cyp1a1 expression from in the promoter To the of in by chromium of B[a]P gene we Cyp1a1 and in cells with or with Cyp1a1 induced by effect that was cells with 50 chromium to B[a]P but not B[a]P was the effect of chromium in the of was induced by B[a]P as but was to chromium that in the Cyp1a1 promoter for the of gene induction by of the cells with led to a of for chromium B[a]P These results that of gene expression was to result from with chromatin associated with the assembly of transcription or the of transcription at the Chromium B[a]P-dependent and of p300 with the Ah at the Cyp1a1 has shown that chromium does not block the of with binding sites in the Cyp1a1 enhancer A. A. Mol. Carcinog. PubMed Scopus Google Scholar). more that the transcriptional inhibitory effect of chromium be with chromatin assembly and of the enhancer by the complex. the of the block by we that chromium with the of with this the we that chromium the of gene expression from of the and to the complex. To chromium we used the the enhancer as as the promoter sequences of the mouse Cyp1a1 in transient assays with expression for p300 and with the chromatin reporter be to to chromium in a as the Cyp1a1 the tested expression in cells and from to over those in cells with with chromium was by with 50 chromium These results that of by the and possibly the release of was by chromium. To this we used on the of the Cyp1a1 the cis-acting enhancer and and and the promoter sequences of the transcription the transcriptional associated with For Hepa-1 cells to to 50 chromium, to or to 50 chromium 1 by at for chromatin was and with to and was and by using the enhancer or the promoter with and be binding of and to enhancer chromatin was induced by B[a]P as by the in enhancer sequences in the with A. A. Mol. Carcinog. PubMed Scopus Google of the binding was in the binding of the complex to promoter sequences in the was by chromium Chromium no effect on or binding to enhancer or promoter These results that chromium a transcriptional block by the promoter with the of complexes to the as for Cyp1a1 Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with this immunoprecipitation with that p300 with enhancer or promoter chromatin in cells and that a block of to those in in cells with chromium in immunoprecipitation with a of HDAC-1 binding at the enhancer but a high at the was by B[a]P with chromium the release of from the with those of the of B[a]P chromium more than the of promoter chromatin that was to These results that of gene expression results from the of at the promoter chromatin and the of p300 in the of the transcriptional complex with promoter assays of Cyp1a1 enhancer and promoter-proximal Hepa-1 cells with B[a]P for 50 chromium for or 50 chromium for to with B[a]P for assays using and HDAC-1 complexes from protein and to a known of was to the to for of Cyp1a1 promoter a of in the by and the to and to using The of the used for is shown in immunoprecipitation with and The of from of the to that the was the in immunoprecipitation with and of is shown in the The results in this that of Ah expression by chromium is a that to at 50 genes involved in a variety of at the transcriptional at for the genes, and tested by that this be the for the genes induction was to by chromium. These results and that that chromium with of inducible gene transcription (4Wetterhahn K.E. Hamilton J.W. Aiyar J. Borges K.M. Floyd R. Biol. Trace Elem. Res. 1989; 21: 405-411Crossref PubMed Scopus (75) Google Scholar, 7Alcedo J.A. Misra M. Hamilton J.W. Wetterhahn K.E. Carcinogenesis. 1994; 15: 1089-1092Crossref PubMed Scopus (27) Google Scholar, 8Hamilton J.W. Wetterhahn K.E. Mol. Carcinog. 1989; 2: 274-286Crossref PubMed Scopus (86) Google Scholar, 10Wetterhahn K.E. Hamilton J.W. Sci. Total Environ. 1989; 86: 113-129Crossref PubMed Scopus (113) Google Scholar, 11McCaffrey J. Wolf C.M. Hamilton J.W. Mol. Carcinog. 1994; 10: 189-198Crossref PubMed Scopus (32) Google Scholar). The evidence from chromium indicates that of chromium the and that transcription in isolated is to as is the in of evidence that the at the of the promoter and with the transcriptional assembly cells the presence of the Cyp1a1 enhancer in the reporter expression to be inducible by the of the promoter sequences to by chromium, effect on the Cyp1a1 These not the to the Cyp1a1 but a for HDAC-1 in of gene expression, to be blocked in by of with chromium to be reduced by cells to stable trivalent chromium. experimental we not are to or associated with chromium the Cr(V) and is that the intermediate oxidation of chromium are not for the of and but a more for effects on gene expression. and have shown that of from the of Cr(VI) to Cr(V) and of binding in human and cells J. Y. PubMed Scopus Google Scholar, Hamilton J.W. Mol. Carcinog. 1999; PubMed Scopus Google Scholar, J. Y. Carcinogenesis. PubMed Scopus Google gene expression is not chromium blocks the binding of the to a transcriptional co-activator with with is for transcriptional J.A. Broderick R.J. Wang Y. Barchowsky A. J. Biol. Chem. 1999; 274: 36207-36212Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Cr(VI) has been found to the of without affecting or inducible binding to D. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the Ah receptor from Hepa-1 cells with chromium to induction to bind to in assays A. A. Mol. Carcinog. PubMed Scopus Google Scholar) or to as found in results by is that chromium the of that the of transcriptional than the binding of transcription to The transduction is by several nuclear the the and chromatin such as A. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Y. J. PubMed Scopus Google Scholar, J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, Gene 1999; Google Scholar, Wang J. Mol. Biol. 2002; PubMed Scopus Google Scholar, D. 1999; PubMed Scopus Google Scholar, 2002; PubMed Scopus Google Scholar, J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). transient reporter of these the effect of chromium on expression, effect in of gene expression was blocked by chromium, that chromium with the or the binding of to the transcriptional complex. assays this and revealed a for HDAC-1 in the of gene expression. The binding of and to enhancer and to promoter chromatin was reduced by chromium to of the in the of HDAC-1 and p300 with chromatin was more by chromium. p300 binding to enhancer or promoter chromatin was by by B[a]P effect that was blocked by chromium to B[a]P HDAC-1 was in the promoter of or was reduced to by B[a]P but the cells with chromium to B[a]P These results to that chromium blocks the release of HDAC-1 from the Cyp1a1 a of histone and transcriptional and the of with histone and transcriptional have shown that HDAC-1 and are to sites associated with sites J. PubMed Google Scholar). analysis of the Cyp1a1 promoter the presence of multiple of have been shown to be and to with and in the induction of the Cyp1a1 gene A. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is to that chromium, known to and A. M. Carcinogenesis. PubMed Scopus Google Scholar, Misra Mol. 1999; PubMed Scopus Google Scholar, Xu J. Patierno Mol. PubMed Scopus Google Scholar, K.M. B.W. Hamilton J.W. Cancer Res. Google may be to to of a of or in the Cyp1a1 the of to in histone on a 2002; PubMed Scopus Google Scholar, D. M. 2002; PubMed Scopus Google be to this analysis results that in the process of gene the complex at the enhancer with promoter These are with a of Cyp1a1 and with results by and Y. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is that the expression of this gene is in a not by the of a receptor complex but by the effect of HDAC-1 at the is of We and for of the and with we for and on the analysis of microarray and and for of human expression and and