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Molecular and Cellular Biology, September 2006, p. 6535-6546, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00267-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

A Single Base Difference between Pit-1 Binding Sites at the hGH Promoter and Locus Control Region Specifies Distinct Pit-1 Conformations and Functions

Brian M. Shewchuk,1,{dagger} Yugong Ho,1 Stephen A. Liebhaber,1,2 and Nancy E. Cooke1,2*

Departments of Genetics,1 Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania 191042

Received 13 February 2006/ Returned for modification 22 March 2006/ Accepted 20 June 2006

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.

* Corresponding author. Mailing address: 752b Clinical Research Bldg., University of Pennsylvania School of Medicine, 415 Curie Blvd., Philadelphia, PA 19103. Phone: (215) 898-4425. Fax: (215) 573-5157. E-mail: necooke{at}mail.med.upenn.edu.

{dagger} Present address: Department of Biochemistry and Molecular Biology, East Carolina University School of Medicine, Greenville, NC 27834.

Molecular and Cellular Biology, September 2006, p. 6535-6546, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00267-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Zhu, X., Gleiberman, A. S., Rosenfeld, M. G. (2007). Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks. Physiol. Rev. 87: 933-963 [Abstract] [Full Text]  


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