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J Biol Chem, Vol. 275, Issue 18, 13827-13834, May 5, 2000
From the 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
Targeted Recruitment of Histone Acetyltransferase Activity to a
Locus Control Region*
§,§¶
Howard Hughes Medical Institute and the
§ Departments of Genetics and Medicine, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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.
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