Abstract
The TATA box element is not only important for establishing basal levels of transcription, but it can also be used to modulate cell type or stage specific gene activity. In the case of the human osteocalcin gene, which is transcriptionally repressed by glucocorticoids, a specific binding element for the glucocorticoid receptor (GR) overlaps a noncanonical TATA box. In the present study, the relevance and function of the TATA element in glucocorticoid-mediated repression of the human osteocalcin gene was characterized. Mutating this noncanonical TATA box into a consensus TATA box within the context of the osteocalcin promoter greatly decreased hormone-dependent transcriptional repression by GR. TATA-binding protein (TBP) bound this mutated element much more strongly suggesting a physiologically relevant role for the weak osteocalcin TATA element in the regulation of this bone specific gene. The optimization of the putative transcription factor IIB recognition site did not affect the level of GR-mediated repression. Our results support a model wherein competitive DNA binding of GR and TBP for their overlapping sites explains conditional repression of the osteocalcin gene by glucocorticoids.
Highlights
Transcription of RNA polymerase II-dependent genes requires, in addition to the enzyme itself, a number of general factors that form a specific multiprotein complex near the transcription start site by interacting with basal promoter elements
The affinity of the TATA-binding protein (TBP)/TATA box interaction has been proposed to contribute to promoter strength in vivo and in vitro, and subsequent assembly of the other general transcription factors into a functional preinitiation complex is dependent upon this initial interaction at the TATA box (1, 4 – 6)
One mechanism by which basal levels of transcription are established is through the binding of transcription factor IID (TFIID) to the TATA box
Summary
Function of a Noncanonical TATA Box sequence of osteocalcin TATA box on glucocorticoid-mediated transcription repression of osteocalcin gene activity. We demonstrate that mutating the osteocalcin TATA box into a consensus TATA element greatly diminished repression by hormone-activated GR. The mutation does not influence the specific GR binding suggesting that the osteocalcin TATA box has an active function in the regulatory process. We present preliminary evidence that suggests that displacement of another polymerase II general transcription factor, TFIIB, is not important for regulation of the osteocalcin gene by mutating promoter positions reported to be responsible for efficient TFIIB function
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