Tissue-specific expression of the human CYP19 (aromatase) gene in ovary and adipose tissue of transgenic mice

Abstract

In humans, the CYP19 (aromatase P450) gene is expressed in a number of tissues, including gonads, placenta, adipose tissue, skin and brain. The 5′-untranslated regions (UTR) of CYP19 mRNA transcripts in these tissues are encoded by different tissue-specific first exons, which are alternatively spliced onto a common site just upstream of the start of translation in exon II. In ovary, the 5′-UTR of CYP19 transcripts is encoded by exon IIa, which lies just upstream of exon II, while in adipose, the 5′-UTR of CYP19 transcripts is encoded by exon I.4, which lies >20 kb upstream of exon II. To map genomic sequences required for ovary- and adipose-specific CYP19 expression, fusion genes containing 2700, 278 and 43 bp of DNA flanking the 5′-end of ovary-specific exon IIa, or 348 bp of 5′- flanking DNA and 170 bp of adipose-specific exon I.4 were linked to the human growth hormone ( hGH) gene, as reporter, and introduced into transgenic mice. We observed that CYP19(IIa):hGH fusion genes containing as little as 278 bp of exon IIa 5′-flanking sequence were expressed at high levels in an ovary-specific manner in transgenic mice, while the CYP19(IIa) −43:hGH fusion gene was not expressed in any tissue. These results suggest that sequences between −43 and −278 bp upstream of exon IIa mediate ovary-specific CYP19 gene expression. In mice carrying the CYP19(I.4) −348:hGH fusion gene, transgene expression was detected in skin and in mammary adipose, but not in any of the other tissues examined. These results indicate that genomic elements within −348 and +170 bp of adipose-specific exon I.4 mediate adipose- and skin-specific CYP19 gene expression. Studies are in progress using transgenic mice to further define the response elements that mediate ovary and adipose-specific hCYP19 gene expression.