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Blood, 1 November 2000, Vol. 96, No. 9, pp. 3040-3048
HEMATOPOIESIS
A minimal c-fes cassette directs myeloid-specific
expression in transgenic mice
Ahlke Heydemann,
Soren Warming,
Cynthia Clendenin,
Kirsten Sigrist,
J. Peter Hjorth, and
M. Celeste Simon
From the Departments of Molecular Genetics and Cell
Biology and Medicine, and Howard Hughes Medical Institute, University
of Chicago, Chicago, IL; and the Department of Molecular and Structural
Biology, University of Aarhus, Aarhus, Denmark.
The c-fes proto-oncogene encodes a 92-kd protein
tyrosine kinase whose expression is restricted largely to myeloid and
endothelial cells in adult mammals. A 13.2-kilobase (kb) human
c-fes genomic fragment was previously shown to contain
cis-acting element(s) sufficient for a locus control
function in bone marrow macrophages. Locus control regions (LCRs)
confer transgene expression in mice that is integration site
independent, copy number dependent, and similar to endogenous murine
messenger RNA levels. To identify sequences required for this LCR,
c-fes transgenes were analyzed in mice.
Myeloid-cell-specific, deoxyribonuclease-I-hypersensitive sites localized to the 3' boundary of exon 1 and intron 3 are required to confer high-level transgene expression comparable to
endogenous c-fes, independent of integration site. We
define a minimal LCR element as DNA sequences (nucleotides +28 to +2523 relative to the transcription start site) located within intron 1 to
intron 3 of the human locus. When this 2.5-kb DNA fragment was linked
to a c-fes complementary DNA regulated by its own
446-base-pair promoter, integration-site-independent,
copy-number-dependent transcription was observed in myeloid cells in
transgenic mice. Furthermore, this 2.5-kb cassette directed expression
of a heterologous gene (enhanced green fluorescent protein) exclusively
in myeloid cells. The c-fes regulatory unit represents a
novel reagent for targeting gene expression to macrophages and
neutrophils in transgenic mice.
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