Dinucleotide Polymorphisms Present in the 5’-Flanking Region of the Human H2 Relaxin Gene, but not in the Corresponding Region of the H1 Gene

Abstract

Relaxin is a peptide hormone that, in humans, is encoded by two genes referred to as H1 and H2, both located into chromosome 9p24.1. We have searched for polymorphisms in the 5’-flanking sequence of these genes. Both genes possess a CT repeat followed by a GT repeat. CT and GT repeats of the H2 gene are longer than those of the H1 gene. Moreover, CT and GT repeats of the H2 gene, but not those of the H1 gene, show length polymorphism. Protein-DNA interaction experiments suggest that difference between the H1 and H2 GT repeats may have arisen because the requirements of the transcriptional regulation of the two genes are different.

Polymorphisms - Microsatellites - Relaxin - Protein-DNA Interaction

References

• 1 Isaacs N, James R, Niall H. et al . Relaxin and its structural relationship to insulin.  Nature. 1978;  271 278-281
• 2 Osheroff P L, Ho W H. Expression of relaxin mRNA and relaxin receptors in postnatal and adult rat brains and hearts. Localization and developmental patterns.  J Biol Chem.. 1993;  268 15 193-15 199
• 3 Yang R H, Bunting S, Wyss J M, Berecek K H, Zhang L, Jin H. Pressor and bradycardic effects of centrally administered relaxin in conscious rats.  Am J Hypertens. 1995;  8 375-381
• 4 Bani D. Relaxin: a pleiotropic hormone.  Gen Pharmacol. 1997;  28 13-22
• 5 Zhao L, Roche P J, Gunnerson J M. et al . Mice without a functional relaxin gene are unable to deliver milk to their pups.  Endocrinology. 1999;  140 445-453
• 6 Crawford R J, Hudson P, Shine J, Niall H D, Eddy R L, Shows T B. Two human relaxin genes are on chromosome 9.  EMBO J. 1984;  3 2341-2345
• 7 Crawford R J, Hammond V E, Roche P J, Johnston P D, Tregear G W. Structure of rhesus monkey relaxin predicted by analysis of the single-copy rhesus monkey relaxin gene.  J Mol Endocrinol. 1989;  3 169-174
• 8 Evans B A, Fu P, Tregear G W. Characterization of two relaxin genes in the chimpanzee.  J Endocrinol. 1994;  140 385-392
• 9 Garibay-Tupas J L, Csiszàr K, Fox M, Povey S, Bryant-Greenwood G D. Analysis of the 5’-upstream regions of the human relaxin H1 and H2 genes and their chromosomal localization on chromosome 9p24.1 by radiation hybrid and breakpoint mapping.  J Mol Endocrinol. 1999;  23 355-365
• 10 Gunnersen J M, Roche P J, Tregear G W, Crawford R J. Characterization of human relaxin gene regulation in the relaxin-expressing human prostate adenocarcinoma cell line LNCaP.FGC.  J Mol Endocrinol. 1995;  15 153-166
• 11 Garibay-Tupas J L, Bao S, Kim M T, Tashima L S, Bryant-Greenwood G D. Isolation and analysis of the 3’-untranslated regions of the human relaxin H1 and H2 genes.  J Mol Endocrinol. 2000;  24 241-252
• 12 Rothenburg S, Koch-Nolte F, Rich A, Haag F. A polymorphic dinucleotide repeat in the rat nucleolin gene forms Z-DNA and inhibits promoter activity.  PNAS. 2001;  31 8985-8990
• 13 Arnold R, Maueler W, Bassili G, Lutz M, Burke L, Epplen T J, Renkawitz R. The insulator protein CTCF represses transcription on binding to the (gt)(22)(ga)(15) microsatellite in intron 2 of the HLA-DRB1(*)0401 gene.  Gene. 2000;  8 209-214
• 14 Akai J, Kimura A, Hata R I. Transcriptional regulation of the human type I collagen alpha2 (COL1A2) gene by the combination of two dinucleotide repeats.  Gene. 1999;  18 65-73
• 15 Fabbro D, Pellizzari L, Mercuri S, Tell G, Damante G. Pax-8 protein levels regulate thyroglobulin gene expression.  J Mol Endocrinol. 1998;  21 347-354
• 16 Weber J L, Wong C. Mutation of short tandem repeats.  Hum Mol Genet. 1993;  2 1123-1128
• 17 Ellegren H. Heterogeneous mutation processes in human microsatellite DNA sequences.  Nat Genet. 2000;  24 400-402
• 18 Weber J L. Informativeness of human (dC-dA)n and (dG-dT)n polymorphisms.  Genomics. 1990;  7 524-530
• 19 Welsh J B, Zarrinkar P P, Sapinoso L M, Kern S G, Behling C A, Monk B J, Lockhart D J, Burger R A, Hampton G M. Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer.  PNAS. 2001;  98 1176-1181
• 20 Kozmik Z, Kurzbauer R, Dörfler P, Busslinger M. Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties.  Mol Cell Biology. 1993;  13 6024-6035
• 21 Zannini M, Francis-Lang H, Plachov D, di Lauro R. Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters.  Mol Cell Biology. 1992;  12 4230-4241
• 22 Pellizzari L, Tell G, Damante G. Co-operation between the PAI and RED subdomains of Pax-8 in the interaction with the thyroglobulin promoter.  Biochem J. 1999;  15 253-262.
• 23 Pellizzari L, Fabbro D, Lonigro R, di Lauro R, Damante G. A network of specific minor-groove contacts is a common characteristic of paired-domain-DNA interactions.  Biochem J. 1996;  315 363-367.
• 24 Bogic L V, Yamamoto S Y, Millar L K, Bryant-Greenwood G D. Developmental regulation of the human relaxin genes in the decidua and placenta: overexpression in the preterm premature rupture of the fetal membranes.  Biol Reprod. 1997;  57 908-920
• 25 Millar L K, Boesche M H, Yamamoto S Y, Killeen J, DeBuque L, Chen R, Bryant-Greenwood G D. A relaxin-mediated pathway to preterm premature rupture of the fetal membranes that is independent of infection.  Am J Obstet Gynecol. 1998;  179 126-134