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Blood, 1 August 2001, Vol. 98, No. 3, pp. 610-617
HEMATOPOIESIS
Localization of distal regulatory domains in the
megakaryocyte-specific platelet basic protein/platelet factor 4 gene
locus
Chunyan Zhang,
Michael A. Thornton,
M. Anna Kowalska,
Bruce S. Sachis,
Michael Feldman,
Mortimer Poncz,
Steven E. McKenzie, and
Michael P. Reilly
From the The Children's Hospital of Philadelphia,
Department of Pediatrics and Pathology and Laboratory Medicine at the
University of Pennsylvania, and the Cardeza Foundation for Hematologic
Research, Departments of Medicine and Pediatrics, Jefferson Medical
College, Philadelphia, Pennsylvania.
The genes for the related human (h) chemokines, PBP (platelet basic
protein) and PF4 (platelet factor 4), are within 5.3 kilobases (kb) of
each other and form a megakaryocyte-specific gene locus. The hypothesis
was considered that the PBP and PF4 genes share a common distal regulatory region(s) that leads to their high-level megakaryocyte-specific expression in vivo. This study examined PBP and
PF4 expression in transgenic mice using 4 distinct human PBP/PF4 gene locus constructs. These studies showed that
within the region studied there was sufficient information to regulate tissue-specific expression of both hPBP and hPF4. Indeed this region
contained sufficient DNA information to lead to expression levels of
PBP and PF4 comparable to the homologous mouse genes in a
position-independent, copy number-dependent fashion. These studies
also indicated that the DNA domains that led to this expression were
distinct for the 2 genes; hPBP expression is regulated by a region that
is 1.5 to 4.4 kb upstream of that gene. Expression of hPF4 is regulated
by a region that is either intergenic between the 2 genes or
immediately downstream of the hPF4 gene. Comparison of the
available human and mouse sequences shows conserved flanking region
domains containing potential megakaryocyte-related transcriptional factor DNA-binding sites. Further analysis of these regulatory regions
may identify enhancer domains involved in megakaryopoiesis that may be
useful in the selective expression of other genes in megakaryocytes and
platelets as a strategy for regulating hemostasis, thrombosis, and inflammation.
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