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Identification of Essential Subelements in the hHSD17B1 Enhancer: Difference in Function of the Enhancer and That of the hHSD17BP1 Analog Is due to -480C and -486G¹

Biocenter Oulu and World Health Organization Collaborating Centre for Research on Reproductive Health, University of Oulu (S.L., Y.-s.P., H.P., P.N., R.V., P.V.), FIN-90401 Oulu, Finland; the State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences (Y.-s.P.), Haidian, Beijing 100080, China; the Department of Obstetrics and Gynecology, Chulalongkorn Hospital (P.N.), Bangkok 10330, Thailand; and the Department of Biosciences, Division of Biochemistry, FIN-00014, University of Helsinki (P.V.), Finland

Address all correspondence and requests for reprints to: Prof. Pirkko Vihko, World Health Organization Collaborating Centre for Research on Reproductive Health, University of Oulu, P.O. Box 5000, FIN-90401 Oulu, Finland. E-mail: pvihko{at}whoccr.oulu.fi

The function of the gene encoding human 17ß-hydroxysteroid dehydrogenase (17HSD) type 1, the hHSD17B1 gene, is regulated by a cell-specific enhancer at position -662 to -392. The adjacent hHSD17BP1 gene, whose function is not known, contains an analogous region in its 5'-flanking region. The identity between the hHSD17B1 enhancer and the hHSD17BP1 equivalent is as high as 98%, i.e. they differ by only five nucleotides. Results from reporter gene analyses showed that the hHSD17BP1 analog, a pseudoenhancer, has only 10% the activity of the hHSD17B1 enhancer. Furthermore, the results indicate that the reduced function of the pseudoenhancer is a consequence of the presence of G and A at positions -480 and -486, whereas the hHSD17B1 enhancer contains -480C and -486G. In addition, three protected areas were localized to regions -495/-485 (FP1), -544/-528 (FP2), and -589/-571 (FP3) in deoxyribonuclease I footprinting analysis of the hHSD17B1 enhancer. Replacement of the footprinted regions with a nonsense sequence demonstrated that the FP2 region is the most critical for enhancer activity. Mutations of FP2 or a short palindromic region within it led to almost complete abolishment of enhancer activity. We have identified several subelements that are essential for appropriate function of the hHSD17B1 enhancer. The results also show that the hHSD17B1 and hHSD17BP1 genes operate differently despite the high homology between them.

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