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Prepublished online as a Blood First Edition Paper on July 25, 2002; DOI 10.1182/blood-2002-05-1307.
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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3588-3596
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Identification of distal regulatory regions in the human
 IIb gene locus necessary for consistent, high-level
megakaryocyte expression
Michael A. Thornton,
Chunyan Zhang,
Maria A. Kowalska, and
Mortimer Poncz
From the Department of Pediatrics, University of
Pennsylvania School of Medicine, Philadelphia.
The  IIb/ 3-integrin receptor is present at high levels only in
megakaryocytes and platelets. Its presence on platelets is critical for
hemostasis. The tissue-specific nature of this receptor's expression
is secondary to the restricted expression of IIb, and studies of the
IIb proximal promoter have served as a model of a
megakaryocyte-specific promoter. We have examined the IIb gene locus for distal regulatory elements. Sequence comparison between
the human (h) and murine (m) IIb loci revealed high levels of
conservation at intergenic regions both 5' and 3' to the IIb gene. Additionally, deoxyribonuclease (DNase) I sensitivity
mapping defined tissue-specific hypersensitive (HS) sites that
coincide, in part, with these conserved regions. Transgenic mice
containing various lengths of the hIIb gene locus, which included or
excluded the various conserved/HS regions, demonstrated that the
proximal promoter was sufficient for tissue specificity, but that a
region 2.5 to 7.1 kb upstream of the hIIb gene was necessary
for consistent expression. Another region 2.2 to 7.4 kb downstream of
the gene enhanced expression 1000-fold and led to levels of hIIb
mRNA that were about 30% of the native mIIb mRNA level. These
constructs also resulted in detectable hIIb/m3 on the platelet
surface. This work not only confirms the importance of the proximal
promoter of the IIb gene for tissue specificity, but also
characterizes the distal organization of the IIb gene locus and
provides an initial localization of 2 important regulatory regions
needed for the expression of the IIb gene at high levels
during megakaryopoiesis.
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