Human Sex Hormone-binding Globulin Promoter Activity Is Influenced by a (TAAAA) Repeat Element within an Alu Sequence

Sex hormone-binding globulin (SHBG) is the major sex steroid-binding protein in human plasma and is produced by the liver. Plasma SHBG levels vary considerably between individuals and are influenced by hormonal, metabolic, and nutritional factors. We have now found that a (TAAAA)n pentanucleotide repeat, located within an alu sequence at the 5′ boundary of the human SHBG promoter, influences its transcriptional activity in association with downstream elements, including an SP1-binding site. Furthermore, SHBG alleles within the general population contain at least 6–10 TAAAA repeats, and the transcriptional activity of a human SHBGpromoter-luciferase reporter construct containing 6 TAAAA repeats was significantly lower than for similar reporter constructs containing 7–10 TAAAA repeats when tested in human HepG2 hepatoblastoma cells. This difference in transcriptional activity reflected the preferential binding of a 46-kDa liver-enriched nuclear factor to an oligonucleotide containing 6 rather than 7–10 TAAAA repeats. Thus, a (TAAAA)n element within the humanSHBG promoter influences transcriptional activity in HepG2 cells and may contribute to differences in plasma SHBG levels between individuals. Sex hormone-binding globulin (SHBG) is the major sex steroid-binding protein in human plasma and is produced by the liver. Plasma SHBG levels vary considerably between individuals and are influenced by hormonal, metabolic, and nutritional factors. We have now found that a (TAAAA)n pentanucleotide repeat, located within an alu sequence at the 5′ boundary of the human SHBG promoter, influences its transcriptional activity in association with downstream elements, including an SP1-binding site. Furthermore, SHBG alleles within the general population contain at least 6–10 TAAAA repeats, and the transcriptional activity of a human SHBGpromoter-luciferase reporter construct containing 6 TAAAA repeats was significantly lower than for similar reporter constructs containing 7–10 TAAAA repeats when tested in human HepG2 hepatoblastoma cells. This difference in transcriptional activity reflected the preferential binding of a 46-kDa liver-enriched nuclear factor to an oligonucleotide containing 6 rather than 7–10 TAAAA repeats. Thus, a (TAAAA)n element within the humanSHBG promoter influences transcriptional activity in HepG2 cells and may contribute to differences in plasma SHBG levels between individuals. sex hormone-binding globulin nucleotide(s) polyacrylamide gel electrophoresis polymerase chain reaction electrophoretic mobility shift assay dithiothreitol lipoprotein (a) Plasma sex hormone-binding globulin (SHBG)1 binds testosterone and estradiol with high affinity and selectivity, and regulates the access of these sex steroids to their target tissues (1Siiteri P.K. Murai J.T. Hammond G.L. Nisker J.A. Raymoure W.J. Kuhn R.W. Recent Prog. Horm. Res. 1982; 38: 457-510PubMed Google Scholar). Hepatocytes are the primary site of plasma SHBG biosynthesis, and changes in the blood levels of SHBG are influenced by hormonal, as well as metabolic and nutritional status (2Hammond G.L. Endocr. Rev. 1990; 11: 65-79Crossref PubMed Scopus (262) Google Scholar). Low serum SHBG levels are commonly found in women with polycystic ovarian syndrome and disorders characterized by androgen excess (3Anderson D.C. Clin. Endocrinol. 1974; 3: 69-96Crossref PubMed Scopus (964) Google Scholar), and have been reported to be a prognostic indicator for the onset of type II diabetes and cardiovascular disease (4Lim S.C. Caballero A.E. Arora S. Smakowski P. Bashoff E.M. Brown F.M. Logerfo F.W. Horton E.S. Veves A. J. Clin. Endocrinol. Metab. 1999; 84: 4159-4164Crossref PubMed Scopus (56) Google Scholar, 5Skafar D.F. Xu R. Morales J. Ram J. Sowers J.R. J. Clin. Endocrinol. Metab. 1997; 82: 3913-3918Crossref PubMed Scopus (130) Google Scholar). Low serum levels of SHBG are also inherited within families (6Meikle A.W. Stanish W.M. Taylor N. Edwards C.Q. Bishop C.T. Metabolism. 1982; 31: 6-9Abstract Full Text PDF PubMed Scopus (58) Google Scholar,7Jaquish C.E. Blangero J. Haffner S.M. Stern M.P. MacCluer J.W. Metabolism. 1997; 46: 988-991Abstract Full Text PDF PubMed Scopus (30) Google Scholar), and associations between abnormal serum SHBG levels and disease processes may therefore be obscured by genetic differences that contribute to variations in human SHBG gene expression. We have recently characterized two binding sites for HNF-4 and COUP-TF within the human SHBG proximal promoter, which influence its transcriptional activity in human HepG2 hepatoblastoma cells (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). In particular, binding of HNF-4 to a TA-rich sequence close to the transcription start site in liver cells appears to substitute for the TATA-binding protein in the initiation of transcription (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). The possible function of the second HNF-4 binding site in theSHBG proximal promoter is not as clear, but it may contribute to phylogenetic differences in the temporal and tissue-specific expression of SHBG because it lies within a region that is absent in the corresponding region of SHBGgenes in other mammalian species (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Apart from this obvious difference in SHBG promoter sequences between species, the human and rodent SHBG promoters show a remarkable degree of sequence conservation, which only begins to diverge at the boundary of several alu sequences located at about −700 nt from the human SHBG transcription start site (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). This likely represents a functional boundary within the promoter sequence because human SHBG gene sequences containing only 803 nt of promoter sequence are expressed in a spatially and temporally appropriate manner when introduced as transgenes into the mouse genome (9Jänne M. Deol H.K. Power S.G.A. Yee S.-P. Hammond G.L. Mol. Endocrinol. 1998; 12: 123-136Crossref PubMed Scopus (85) Google Scholar, 10Jänne M. Hogeveen K.N. Deol H.K. Hammond G.L. Endocrinology. 1999; 140: 4166-4174Crossref PubMed Scopus (31) Google Scholar). Although the significance of repetitive elements within promoter sequences is unclear, they may contain nuclear factor binding sites that contribute to the regulation of transcription (11Sharan C. Hamilton N.M. Parl A.K. Singh P.K. Chaudhuri G. Biochem. Biophys. Res. Commun. 1999; 265: 285-290Crossref PubMed Scopus (30) Google Scholar, 12Norris J. Fan D. Aleman C. Marks J.R. Futreal P.A. Wiseman R.W. Iglehart J.D. Deininger P.L. McDonnell D.P. J. Biol. Chem. 1995; 270: 22777-22782Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, 13Vansant G. Reynolds W.F. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 8229-8233Crossref PubMed Scopus (141) Google Scholar). By characterizing the upstream region of the human SHBGpromoter, we have now found that a (TAAAA)6 repeat within an alu sequence binds a 46-kDa liver enriched nuclear protein and acts to silence transcription. More importantly, the number of TAAAA repeats at this location is highly variable between individuals within the general population, and the transcriptional activity of the SHBG promoter and the binding of nuclear protein to this element are both directly related to the number of TAAAA repeats. In vitrofootprinting templates of human SHBG promoter upstream regions were produced by digesting a human SHBG fragment (14Hammond G.L. Underhill D.A. Rykse H.M. Smith C.L. Mol. Endocrinol. 1989; 3: 1869-1876Crossref PubMed Scopus (125) Google Scholar) with XhoI and XbaI. This released a 504-base pair region of the SHBG promoter corresponding to −803/−299 nt relative to the transcription start site in the liver (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). This fragment was further digested with HaeIII orHinfI, and the products (−803/−656 ntXhoI-HaeIII, −735/−587 ntHinfI-HinfI, −587/−362 ntHinfI-HinfI, −541/−298 ntHaeIII-XbaI) were cloned into theEcoRV site of pBluescript (Stratagene, La Jolla, CA) in the correct orientation to permit labeling of the sense strand after digestion with HindIII. The HindIII-digested constructs were end-labeled with the Klenow fragment of DNA polymerase I in the presence of [α-32P]dCTP and purified using a NICK™ column (Amersham Pharmacia Biotech, Baie d'Urfé, Québec, Canada). Radiolabeled probes were released from the plasmids by digestion with EcoRI and purified by 6% polyacrylamide gel electrophoresis (PAGE). The DNase I footprinting reactions with mouse liver nuclear extracts were carried out as described previously (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). Hydroxy-radical footprinting with the same extracts was also performed using the −803/−656 ntXhoI-HaeIII region of the human SHBGpromoter (15Tullius T.D. Dombroski B.A. Churchill M.E.A. Kam L. Methods Enzymol. 1987; 155: 537-558Crossref PubMed Scopus (283) Google Scholar, 16O'Halloran T.V. Frantz B. Shin M.K. Ralston D.M. Wright J.G. Cell. 1989; 56: 119-129Abstract Full Text PDF PubMed Scopus (194) Google Scholar). Mouse liver nuclear extracts were used in these and other experiments to characterize and study the regulation of humanSHBG promoter activity because human SHBGtransgenes are expressed efficiently in mouse hepatocytes postnatally (9Jänne M. Deol H.K. Power S.G.A. Yee S.-P. Hammond G.L. Mol. Endocrinol. 1998; 12: 123-136Crossref PubMed Scopus (85) Google Scholar, 10Jänne M. Hogeveen K.N. Deol H.K. Hammond G.L. Endocrinology. 1999; 140: 4166-4174Crossref PubMed Scopus (31) Google Scholar). Human SHBG promoter deletion constructs were generated by amplifying a region from anSHBG fragment (14Hammond G.L. Underhill D.A. Rykse H.M. Smith C.L. Mol. Endocrinol. 1989; 3: 1869-1876Crossref PubMed Scopus (125) Google Scholar) in a polymerase chain reaction (PCR). This was done using a common reverse primer containing anXbaI site (−299) and forward primers (containing anXhoI site) corresponding to various positions in the 5′ promoter region (Table I). These PCR products were digested with XhoI and XbaI and then subcloned into a pSP72 vector (Promega Corp., Madison, WI) containing the −299/+60 nt region of the human SHBGproximal promoter. The entire promoter sequences were then excised withHindIII and XhoI and inserted into a pGL2 Basic luciferase reporter plasmid (Promega).Table ISequences of oligonucleotides used for deleting (A) or mutating (B) human SHBG promoter sequence in the context of luciferase reporter gene constructsA. DescriptionPCR oligonucleotides for promoter deletions−299 reverse5′-GAGGTCTAGAAACAGTCCTCCCCTGCGT−696 forward5′-TGAACTCGAGGGGTCAGGGAGTGGGTGA−670 of sequences sites used for of human SHBG promoter oligonucleotide to the TAAAA introduced into the binding site were a in an sequence M. G. S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). in a sequences sites used for of human SHBG promoter oligonucleotide to the TAAAA introduced into the binding site were a in an sequence M. G. S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). was using a vector containing the −803/−299 nt region of the human SHBGpromoter, to the sequences in were by XhoI digestion and subcloned into the pSP72 vector containing the −299/+60 nt region of the human SHBGpromoter, and the entire promoter sequences were then inserted into pGL2 as described and sequences were by DNA using a (Amersham Pharmacia were from Canada). Human HepG2 hepatoblastoma cells were in with and were with human SHBG reporter constructs and using (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). were and extracts were by of and for of luciferase and were by from a assay to correct for of Mouse liver nuclear protein extracts were to In Google Scholar), and then in and of for in the presence or of oligonucleotides (Table The corresponding end-labeled oligonucleotide probes were then and the binding reaction was to for at was with nuclear for to of or an to were then for at to oligonucleotides were from by and the gel was and to an at of oligonucleotides used in and electrophoretic mobility shift sequences that were using the Klenow fragment of DNA polymerase I and [α-32P]dCTP to In Google Scholar). introduced into were a that an sequence M. G. S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). oligonucleotides J. PubMed Google Scholar) and (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar) binding sites were used as reported by in a sequences that were using the Klenow fragment of DNA polymerase I and [α-32P]dCTP to In Google Scholar). introduced into were a that an sequence M. G. S. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). oligonucleotides J. PubMed Google Scholar) and (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar) binding sites were used as reported by reactions of nuclear protein extracts to oligonucleotides various TAAAA repeats (Table were carried out the same used for a at were to at a of for at of were and were at for and to with and in the and were and to as described from mouse cells and human cells J.D. Res. 11: PubMed Scopus Google Scholar), as well as mouse liver to In Google Scholar), were by and by electrophoresis a (Amersham Pharmacia The was for in a containing and was then in binding and oligonucleotide the (TAAAA)6 sequence in theSHBG upstream promoter (Table was to the binding containing and and was with the for at The was then in and to as described DNA was from blood of human J. Scholar). of the TAAAA repeat region was using PCR with a forward primer within an alu sequence in the humanSHBG promoter (14Hammond G.L. Underhill D.A. Rykse H.M. Smith C.L. Mol. Endocrinol. 1989; 3: 1869-1876Crossref PubMed Scopus (125) Google Scholar), and a reverse primer corresponding to a sequence at nt within the upstream promoter products were by by with The number of TAAAA repeats was by PCR products in the vector Corp., CA) for from the same individuals were also for of SHBG using a assay binding sites for nuclear in the human SHBG upstream promoter were by in footprinting using mouse liver nuclear extracts of these a sequence which a binding site when by using Res. 1995; PubMed Scopus Google Scholar) In a sequence within a binding site by using the R. M. Res. PubMed Scopus Google Scholar). region containing TAAAA repeats, which is to DNase I digestion in the presence or of nuclear lies between and and the boundary of the within the TAAAA repeat region was by footprinting with a mouse liver nuclear protein footprinting of the TAAAA repeat within the upstream region of the human −803/−656 fragment of the humanSHBG promoter was in the or presence of or of mouse liver nuclear protein and was then to DNA The products were purified and a polyacrylamide the products of a reaction as The (TAAAA)6 region and were from and are in between and a oligonucleotide that was by The of this was by of using an oligonucleotide containing a binding site In the major in an reaction was with an The activity with the nuclear factor binding sites by DNase I footprinting in was by to a human SHBGproximal reporter gene construct (8Jänne M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). These constructs were used for transcriptional activity in a human hepatoblastoma that SHBG D.P. J. Clin. Endocrinol. Metab. PubMed Scopus Google Scholar). This that upstream sequences transcriptional activity when with the activity of the proximal promoter In particular, of sequences that as well as a site within and the (TAAAA)6 sequence in and of promoter activity The of transcription by sequences at the 5′ boundary of the upstream promoter to be with the (TAAAA)6 sequence because a in transcription was when it was from the promoter was also that of the binding site (Table within which its with liver nuclear extracts in an not also in a similar in the transcriptional activity of the promoter of the transcriptional activity of the promoter was not further by of TAAAA pentanucleotide repeat in with a binding site within is also to that the presence of appears to have a transcription only in the context of upstream sequences within the promoter tested in an a oligonucleotide the (TAAAA)6 sequence with nuclear factor from mouse liver and be for by oligonucleotides this repeat but not with an DNA sequence further characterize the nuclear binding at this pentanucleotide repeat, a (TAAAA)6 repeat oligonucleotide sequence (Table was used as a for a The a nuclear protein with an of which is enriched in mouse liver nuclear extracts when with nuclear extracts from mouse cells or cells By a nuclear protein with a of was in nuclear extracts and likely represents a nuclear which binds to this sequence of nuclear binding to the (TAAAA)6 repeat from mouse a mouse and cells were a by to a The was with a oligonucleotide the TAAAA pentanucleotide repeats in the 5′ region of the human of of is the In of that the number of TAAAA repeats in the promoters of other human individuals J. J. 1998; PubMed Scopus Google Scholar), we the region of the promoter containing the TAAAA repeat sequence from The of the PCR products that the number of TAAAA repeats is highly variable both within and between individuals and we that the repeat number from 6 to by The serum SHBG in these individuals to their (TAAAA)n were as and Although was obvious between serum SHBG and the number of TAAAA repeats an with two (TAAAA)6 containing SHBG alleles a serum SHBG the number of individuals we have is and was to for that influence serum SHBG as The influence of this transcription was tested in the context of the human SHBG promoter. We found that the activity of human SHBG reporter constructs in HepG2 cells as the number of TAAAA repeats was from to repeat sequences were further in promoter activity were These in promoter activity with repeats is similar to the when the (TAAAA)6 sequence is from the promoter these that the activity is with the presence of only TAAAA repeats. This was by similar experiments using promoter sequences containing only or TAAAA repeats, which also levels of transcriptional activity when with the promoter sequence containing repeats further nuclear factor binding in to the number of TAAAA repeats, we performed a with oligonucleotides the various (6Meikle A.W. Stanish W.M. Taylor N. Edwards C.Q. Bishop C.T. Metabolism. 1982; 31: 6-9Abstract Full Text PDF PubMed Scopus (58) Google Scholar, C.E. Blangero J. Haffner S.M. Stern M.P. MacCluer J.W. Metabolism. 1997; 46: 988-991Abstract Full Text PDF PubMed Scopus (30) Google Scholar, M. Hammond G.L. J. Biol. Chem. 1998; 273: 34105-34114Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, M. Deol H.K. Power S.G.A. Yee S.-P. Hammond G.L. Mol. Endocrinol. 1998; 12: 123-136Crossref PubMed Scopus (85) Google Scholar, 10Jänne M. Hogeveen K.N. Deol H.K. Hammond G.L. Endocrinology. 1999; 140: 4166-4174Crossref PubMed Scopus (31) Google Scholar) of TAAAA repeats in the general population in the presence of mouse liver nuclear protein extracts This that the oligonucleotide containing TAAAA repeats binds nuclear and the major were in Furthermore, the relative of these when oligonucleotides containing than repeats were and this is with the in transcriptional activity of promoters containing than TAAAA repeats The of the using the TAAAA repeat oligonucleotide sequence was by with and the of in the presence of nuclear protein to In of oligonucleotides to not in the of high in the of nuclear protein not The of the major is with a between the oligonucleotide containing the TAAAA repeats and the 46-kDa liver enriched protein as the protein by levels of SHBG in are highly variable between individuals (6Meikle A.W. Stanish W.M. Taylor N. Edwards C.Q. Bishop C.T. Metabolism. 1982; 31: 6-9Abstract Full Text PDF PubMed Scopus (58) Google Scholar). this be by a genetic we the nt of the human SHBG promoter from individuals and with various and disorders in a but found between L. By of human SHBG promoter activity in HepG2 hepatoblastoma cells to a located within an sequence close to the 5′ boundary of the transcription expressed in hepatocytes (9Jänne M. Deol H.K. Power S.G.A. Yee S.-P. Hammond G.L. Mol. Endocrinol. 1998; 12: 123-136Crossref PubMed Scopus (85) Google Scholar). This pentanucleotide repeat been found to vary in number within the human promoter J. J. 1998; PubMed Scopus Google Scholar), and is a association between alleles with this and serum testosterone levels in with polycystic ovarian syndrome and N. D.M. S. D. C. M. S. R. Mol. 1997; PubMed Scopus Google Scholar). this (TAAAA)6 repeat to have a SHBG promoter we the possible that to and it function in with other elements in the upstream region of the human SHBG promoter to influence transcription. The upstream region of the human SHBG promoter transcription in HepG2 and of this activity is with a region between and which the (TAAAA)6 repeat We have that the (TAAAA)6 repeat is for this activity by it or by the number of repeats to the number in the general is also that this activity is downstream promoter elements and appears to an nuclear site within Although is to be an of it in transcriptional with other transcriptional in a manner A. J. 1995; PubMed Scopus Google Scholar, S. M. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). This only appears to promoter activity in association with upstream elements within the promoter. Although that binds to we also that a second protein with a and this not to be with an is therefore possible that with as G. S. M. G. Res. PubMed Scopus Google Scholar, G. S. M. G. J. PubMed Scopus Google Scholar), and this be because acts as a of transcription P. B. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, between and other for a common site within promoter sequences their transcriptional activity G. S. M. G. J. PubMed Scopus Google Scholar). in the number of repeats within several other promoters have been reported to transcription N. M. S. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar) and have been to disease N. D.M. S. D. C. M. S. R. Mol. 1997; PubMed Scopus Google Scholar, N. M. S. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Proc. Natl. Acad. Sci. U. S. 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In experiments of the human SHBG promoter was only in the presence of TAAAA repeats, and this with the preferential binding of a liver-enriched 46-kDa nuclear factor to the (TAAAA)6 repeat Although alleles containing than TAAAA repeats were not in the of individuals we the of SHBG promoters containing or TAAAA repeats also the with the presence of repeats. These that the 46-kDa factor that binds TAAAA repeats with high affinity acts in with downstream elements within the humanSHBG promoter to its transcriptional In a (TAAAA)n repeat within the human SHBG promoter a its transcriptional activity in in HepG2 cells. This contribute to differences in plasma SHBG levels and influence the access of sex steroids to their target Furthermore, variations in the number of TAAAA repeats within regions of other human may contribute to differences in gene expression. The DNA we were from of various and the number of TAAAA repeat elements from 6 to in this of Although was obvious between the number of TAAAA repeat elements and the serum SHBG the number of individuals is to as of were for of TAAAA repeats. to that the of the (TAAAA)n to influence the transcriptional activity of the human SHBG promoter as DNA in experiments may not its activity in the context of DNA within a therefore be to a study to this is with differences in plasma SHBG and to alleles are with sex with to various that influence plasma SHBG We and for their and and Power for

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