A Single Base Difference Between Pit-1 Binding Sites at the Hgh Promoter and Locus Control Region Specifies Distinct Pit-1 Conformations and Functions.
From: University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19103, USA.
Molecular and cellular biology
- Publish Date: Sep 2006
- ISSN: 0270-7306
- Volume: 26
- Issue: 17
- Pages: 6535-46
- Medium: Print
- Language: English
- Citation (JAMA): Shewchuk Brian M, Ho Yugong, Liebhaber Stephen A, et al. A Single Base Difference Between Pit-1 Binding Sites at the Hgh Promoter and Locus Control Region Specifies Distinct Pit-1 Conformations and Functions.. Mol. Cell. Biol. Sep 2006;26:6535-46
Abstract
Activation of the human growth hormone (hGH-N) gene in pituitary somatotropes is mediated by a locus control region (LCR). This LCR is composed of DNase I-hypersensitive sites (HS) located -14.5 kb to -32 kb relative to the hGH-N promoter. HSI, at -14.5 kb, is the dominant determinant of hGH-N expression and is essential for establishment of a 32-kb domain of histone acetylation that encompasses the active hGH locus. This activity is conferred by three binding sites for the POU domain transcription factor Pit-1. These Pit-1 elements are sufficient to activate hGH-N expression in the mouse pituitary. In contrast, Pit-1 sites at the hGH-N promoter are consistently unable to mediate similar activity. In the present study, we demonstrate that the functional difference between the promoter-proximal and the HSI Pit-1 binding sites can be attributed in part to a single base difference. This base affects the conformation of the Pit-1/DNA complex, and reciprocal exchange of the divergent bases between the two sets of Pit-1 elements results in a partial reversal of their transgenic activities. These data support a model in which the Pit-1 binding sites in the hGH LCR allosterically program the bound Pit-1 complex for chromatin activating functions.
Mesh Headings (Keywords): Adenine, Animals, Base Pairing, Base Sequence, Binding Sites, CREB-Binding Protein, Consensus Sequence, Gene Expression, Human Growth Hormone, Locus Control Region, Mice, Mice, Transgenic, Molecular Sequence Data, Mutation, Peptide Hydrolases, Pituitary Gland, Promoter Regions (Genetics), Protein Binding, Protein Conformation, Rats, Thymine, Transcription Factor Pit-1
Check for Full Text / PubMed Unique Identifier (PMID): 16914737
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