TRANSCRIPTIONAL REGULATION OF CYTOCHROME P-450 GENES

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P450 genes are either individually or are constitutively expressed. The inducible genes are usually expressed at low levels in the absence of an inducing agent. Constitutively expressed P450 genes are also developmentally regulated. Typically P450s are absent in livers of animals prior to birth. Immediately after parturition, several P450 genes are activated and become fully expressed within a few days after birth. To understand the mechanism of this developmentally programmed gene activation, the CYP2EI gene is being studied. The upstream DNA of this gene becomes demethylated immediately after birth coincident with its transcription activation. The nuclear transcription factor HNF-I was found to bind to a DNA element immediately adjacent to the CYP2EI promoter and this binding is thought to mediate transcription. Nuclease hypersensitivity analysis indicated that the chromatin of the CYP2EI gene becomes sensitive within one day after birth suggesting that a factor is bound to the DNA. It is still unknown whether demethylation or HNF-I binding is the signal of developmental gene activation. A strain of radiation deletion mice were found that have a deletion of a 1.2 centiMorgan segment of DNA on chromosome 7. These mice die within a few days after birth due to liver failure. Analysis of CYP2EI gene expression revealed that newborn mice homozygous for the deletion do not express CYP2EI. Heterozygotes and homozygous normal mice do produce CYP2EI MRNA. Since the Hnf-1 gene is on chromosome 5, and CYP2EI is on chromosome 7, but proximal to the deleted region in these mice, the lack of CYP2EI gene expression might be due to the binding of a trans-acting transcription factor that is epistatic in the regulatory cascade that includes HNF-I expression.