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Silencing of the Gene for the -Subunit of Human Chorionic Gonadotropin by the Embryonic Transcription Factor Oct-3/4

Departments of Biological Sciences (L.L.) and Animal Sciences and Biochemistry (D.L., M.V., R.M.R.), University of Missouri, Columbia, Missouri 65211

CG is required for maintenance of the corpus luteum during pregnancy in higher primates. As CG is a heterodimeric molecule, some form of coordinated control must be maintained over the transcription of its two subunit genes. We recently found that expression of human CG ß-subunit (hCGß) in JAr human choriocarcinoma cells was almost completely silenced by the embryonic transcription factor Oct-3/4, which bound to a unique ACAATAATCA octameric sequence in the hCGß gene promoter. Here we report that Oct-3/4 is also a potent inhibitor of hCG -subunit (hCG) expression in JAr cells. Oct-3/4 reduced human GH reporter expression from the -170 hCG promoter in either the presence or absence of cAMP by about 70% in transient cotransfection assays, but had no effect on expression from either the -148 hCG or the -99 hCG promoter. Unexpectedly, no Oct-3/4-binding site was identified within the -170 to -148 region of the hCG promoter, although one was found around position -115 by both methylation interference footprinting and electrophoretic mobility shift assays. Site-directed mutagenesis of this binding site destroyed the affinity of the promoter for Oct-3/4, but did not affect repression of the promoter. Therefore, inhibition of hCG gene transcription by Oct-3/4 appears not to involve direct binding of this factor to the site responsible for silencing. When stably transfected into JAr cells, Oct-3/4 reduced the amounts of both endogenous hCG mRNA and protein by 70–80%. Oct-3/4 is therefore capable of silencing both hCG and hCGß gene expression. We suggest that as the trophoblast begins to form, reduction of Oct-3/4 expression permits the coordinated onset of transcription from the hCG and hCGß genes.

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