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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2002-02-0568.
Submitted February 21, 2002
Accepted May 14, 2002
The SCL-complex regulates c-kit expression in hematopoietic cells through functional interaction with Sp1
Eric Lecuyer, Sabine Herblot, Marianne Saint-Denis, Richard Martin, C G Begley, Catherine Porcher, Stuart H Orkin, and Trang Hoang*
Hemopoiesis and Leukemia, Institut de recherches cliniques de Montreal (IRCM), Montreal, PQ, Canada; Departments of Pharmacology, Biochemistry and Molecular Biology, Universite de Montreal, Montreal, PQ, Canada
Hemopoiesis and Leukemia, Institut de recherches cliniques de Montreal (IRCM), Montreal, PQ, Canada
Telethon Institute for Child Health Research, Center for Child Health Research, The University of Western Australia, West Perth, WA, Australia
Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Headington, Oxford, United Kingdom
Howard Hughes Medical Institute, The Children`s Hospital, Harvard Medical School, Boston, MA, USA
* Corresponding author; email: HoangT{at}ircm.qc.ca.
The combinatorial interaction between transcription factors is believed to determine hematopoietic cell fate. SCL/TAL1 is a tissue-specific bHLH factor that plays a central function during hematopoietic development; however, its target genes and molecular mode of action remain to be elucidated. Here we show that SCL and the c-Kit receptor are co-expressed in hematopoietic progenitors at the single cell level, and that SCL induces c-kit in chromatin, as ectopic SCL expression in transgenic mice sustains c-kit transcription in developing B lymphocytes in which both genes are normally down-regulated. Through transient transfection assays and co-immunoprecipitation of endogenous proteins, we define the role of SCL as a nucleation factor for a multi-factorial complex (SCL-complex) that specifically enhances c-kit promoter activity without affecting the activity of myelo-monocytic promoters. This complex, containing hematopoietic-specific (SCL, LMO2, GATA 1/2) and ubiquitous (E2A, Ldb-1) factors, is tethered to DNA via a Sp1 motif, through direct interactions between elements of the SCL-complex and the Sp1 zinc finger protein. Furthermore, we demonstrate by chromatin immunoprecipitation that SCL, E2A, and Sp1 specifically co-occupy the c-kit promoter in vivo. We therefore conclude that c-kit is a direct target of the SCL-complex. Proper activation of the c-kit promoter depends on the combinatorial interaction of all members of the complex. Since SCL is down-regulated in maturing cells while its partners remain expressed, our observations suggest that loss of SCL inactivates the SCL-complex, which may be an important event in the differentiation of pluripotent hematopoietic cells.
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