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This version published online on April 29, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0461
Molecular Endocrinology Vol. 0, No. 2004 200304611-
doi:10.1210/me.2003-0461
Copyright © 2004 by the Endocrine Society.
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Submitted on December 6, 2003
Accepted on April 19, 2004

Regulation of the human secretin gene is controlled by the combined effects of CpG methylation, Sp1/Sp3 ratio and the E-Box element

LEO TSZ-ON LEE*, KIAN-CHENG TAN-UN, RONALD TING-KAI PANG, DAVID TAI-WAI LAM, and BILLY KWOK-CHONG CHOW

Department of Zoology, University of Hong Kong, Hong Kong, PRC.

* To whom correspondence should be addressed. E-mail: bkcc{at}hkusua.hku.hk.

To unravel the mechanisms that regulate the human secretin gene expression, in this study, we have used secretin-expressing (HuTu-80 cells, human duodenal adenocarcinoma) and non-secretin-expressing (PANC-1 and HepG2 cells) cell models for in vitro and in vivo analyses. By transient transfection assays, within the promoter region (-11 to \-341 from ATG, relative to the ATG initiation codon), we have initially identified several functional motifs including an E-box and 2 GC-Boxes. Results from gel mobility shift and ChIP assays confirmed further that NeuroD, E2A, Sp1 and Sp3 bind to these E- and GC-Boxes in HuTu-80 cells in vitro and in vivo while only high levels of Sp3 is observed to bind the promoter in HepG2 cells. In addition, over-expression of Sp3 resulted in a dose-dependent repression of the Sp1-mediated transactivation. Collectively, these data suggest that the Sp1/Sp3 ratio is instrumental to controlling secretin gene expression in secretin-producing and non-secretin-producing cells. The functions of GC-box and Sp-proteins prompted us to investigate the possible involvement of DNA methylation in regulating this gene. Consistent with this idea, we found a putative CpG island (-336 to 262 from ATG) that overlaps with the human secretin gene promoter. By methylation specific PCR, all the CpG dinucleotides (26 of them) within the CpG island in HuTu-80 cells are un-methylated while all these sites are methylated in PANC-1 and HepG2 cells. The expressions of secretin in PANC-1 and HepG2 cells were subsequently found to be significantly activated by a demethylation agent, 5'-Aza-dC. Taken together, our data indicate that the human secretin gene is controlled by the in vivo Sp1/Sp3 ratio and the methylation status of the promoter.




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