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Blood, 15 November 2001, Vol. 98, No. 10, pp. 2958-2965
HEMATOPOIESIS
Regulation of the PU.1 gene by distal
elements
Youlin Li,
Yutaka Okuno,
Pu Zhang,
Hanna S. Radomska,
Hui-min Chen,
Hiromi Iwasaki,
Koichi Akashi,
Michael J. Klemsz,
Scott R. McKercher,
Richard A. Maki, and
Daniel G. Tenen
From the Harvard Institutes of Medicine, Harvard
Medical School; and Dana Farber Cancer Institute; both of Boston, MA;
Department of Microbiology and Immunology, Indiana University School of
Medicine, Indianapolis, IN; and The Burnham Institute, La Jolla, CA.
The transcription factor PU.1 (also known as Spi-1) plays a
critical role in the development of the myeloid lineages, and myeloid
cells derived from PU.1 / animals are blocked at the
earliest stage of myeloid differentiation. Expression of the PU.1 gene
is tightly regulated during normal hematopoietic development, and
dysregulation of PU.1 expression can lead to erythroleukemia. However,
relatively little is known about how the PU.1 gene is regulated in
vivo. Here it is shown that myeloid cell type-specific
expression of PU.1 in stable cell lines and transgenic animals is
conferred by a 91-kilobase (kb) murine genomic DNA fragment that
consists of the entire PU.1 gene (20 kb) plus approximately 35 kb of
upstream and downstream sequences, respectively. To further map the
important transcriptional regulatory elements, deoxyribonuclease I
hypersensitive site mapping studies revealed at least 3 clusters in the
PU.1 gene. A 3.5-kb fragment containing one of these deoxyribonuclease
I hypersensitive sites, located  14 kb 5' of the transcriptional start
site, conferred myeloid cell type-specific expression in stably
transfected cell lines, suggesting that within this region is an
element important for myeloid specific expression of PU.1. Further
analysis of this myeloid-specific regulatory element will provide
insight into the regulation of this key transcriptional regulator and
may be useful as a tool for targeting expression to the myeloid lineage.
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