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Molecular and Cellular Biology, March 2004, p. 1870-1883, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.1870-1883.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The scl +18/19 Stem Cell Enhancer Is Not Required for Hematopoiesis: Identification of a 5' Bifunctional Hematopoietic-Endothelial Enhancer Bound by Fli-1 and Elf-1

Department of Hematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY,¹ Department of Anatomy, Birmingham University Medical School, Birmingham B15 2TT, United Kingdom,⁴ Telethon Institute for Child Health Research, Centre for Child Health Research and WAIMR, University of Western Australia, West Perth, Western Australia 6872, Australia,⁵ Amgen, Inc., Thousand Oaks, California 91320-1799,⁶ Centro Andaluz de Biologia del Desarrollo, Universidad Pablo de Olavide, Seville,² Centro Nacional de Biotechnologia, Canto Blanco, 28024 Madrid, Spain³

Received 7 August 2003/ Returned for modification 26 September 2003/ Accepted 4 December 2003

Analysis of cis-regulatory elements is central to understanding the genomic program for development. The scl/tal-1 transcription factor is essential for lineage commitment to blood cell formation and previous studies identified an scl enhancer (the +18/19 element) which was sufficient to target the vast majority of hematopoietic stem cells, together with hematopoietic progenitors and endothelium. Moreover, expression of scl under control of the +18/19 enhancer rescued blood progenitor formation in scl^-/- embryos. However, here we demonstrate by using a knockout approach that, within the endogenous scl locus, the +18/19 enhancer is not necessary for the initiation of scl transcription or for the formation of hematopoietic cells. These results led to the identification of a bifunctional 5' enhancer (-3.8 element), which targets expression to hematopoietic progenitors and endothelium, contains conserved critical Ets sites, and is bound by Ets family transcription factors, including Fli-1 and Elf-1. These data demonstrate that two geographically distinct but functionally related enhancers regulate scl transcription in hematopoietic progenitors and endothelial cells and suggest that enhancers with dual hematopoietic-endothelial activity may represent a general strategy for regulating blood and endothelial development.

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