Tissue-specific expression of the human CYP19 (aromatase) gene in ovary and adipose tissue of transgenic mice.
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 +170bp 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.
Hinshelwood
M M
MM
Department of Obstetrics and Gynecology, University of Texas, Southwestern Medical Center, University of Texas, 5323 Harry Hines Boulevard, Dallas, TX 75390-9038, USA.
Mendelson
C R
CR
D020121:5' Untranslated Regions; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D001141:Aromatase / Q000235:genetics*; D019677:Artificial Gene Fusion; D005091:Exons; D005260:Female; D015870:Gene Expression; D019382:Human Growth Hormone / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D010053:Ovary / Q000201:enzymology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
D020121:5' Untranslated Regions; D012333:RNA, Messenger; D019382:Human Growth Hormone; D001141:Aromatase