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J Biol Chem, Vol. 275, Issue 18, 13827-13834, May 5, 2000

Targeted Recruitment of Histone Acetyltransferase Activity to a Locus Control Region*

Felice ElefantDagger §, Nancy E. Cooke§, and Stephen A. LiebhaberDagger §

From the Dagger  Howard Hughes Medical Institute and the § Departments of Genetics and Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Locus control regions (LCRs) are capable of activating target genes over substantial distances and establishing autonomously regulated chromatin domains. The basis for this action is poorly defined. Human growth hormone gene (hGH-N) expression is activated by an LCR marked by a series of DNase I-hypersensitive sites (HSI-III and HSV) in pituitary chromatin. These HSs are located between -15 and -32 kilobases (kb) relative to the hGH transcription start site. To establish a mechanistic basis for hGH LCR function, we carried out acetylation mapping of core histones H3 and H4 in chromatin encompassing the hGH cluster. These studies revealed that the entire LCR was selectively enriched for acetylation in chromatin isolated from a human pituitary somatotrope adenoma and in pituitaries of mice transgenic for the hGH locus, but not in hepatic or erythroid cells. Quantification of histone modification in the pituitary revealed a dramatic peak at HSI/II, the major pituitary-specific hGH LCR determinant (-15 kb), with gradually decreasing levels of modification extending from this site in both 5'- and 3'-directions. The 5'-border of the acetylated domain coincided with the 5' most hGH LCR element, HSV (-34 kb); and the 3'-border included the expressed hGH-N gene, but did not extend farther 3' into the placenta-specific region of the gene cluster. These data support a model of LCR function involving targeted recruitment and subsequent spreading of histone acetyltransferase activity to encompass and activate a remote target gene.

* This work was supported by National Institutes of Health Grant HD25147 (to N. E. C. and S. A. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Depts. of Genetics and Medicine, University of Pennsylvania School of Medicine, Rm. 428, Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-7834; Fax: 215-573-5157; E-mail: liebhaber@mail.med.upenn.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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