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Blood, 15 December 2007, Vol. 110, No. 13, pp. 4188-4197.
Prepublished online as a Blood First Edition Paper on September 6, 2007; DOI 10.1182/blood-2007-07-100883.
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Submitted July 11, 2007
Accepted September 3, 2007
Runx1-mediated hematopoietic stem cell emergence is controlled by a Gata/Ets/SCL-regulated enhancer
Wade T. Nottingham, Andrew Jarratt, Matthew Burgess, Caroline L. Speck, Jan-Fang Cheng, Shyam Prabhakar, Eddy M. Rubin, Pik-Shan Li, Jackie Sloane-Stanley, John Kong-a-San, and Marella F.T.R. de Bruijn*
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom
Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, United States
US Department of Energy Joint Genome Institute, Walnut Creek, CA, United States
Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands
* Corresponding author; email: marella.debruijn{at}imm.ox.ac.uk.
The transcription factor Runx1/AML1 is an important regulator of hematopoiesis and is critically required for the generation of the first definitive HSCs in the major vasculature of the mouse embryo. As a pivotal factor in HSC ontogeny, its transcriptional regulation is of high interest but is largely undefined. In this study we used a combination of comparative genomics and chromatin analysis to identify a highly conserved 531bp enhancer located at position +23.5 in the first intron of the 224kb mouse Runx1 gene. We show that this enhancer contributes to the early hematopoietic expression of Runx1. Transcription factor binding in vivo and analysis of the mutated enhancer in transient transgenic mouse embryos implicate Gata2 and Ets proteins as critical factors for its function. We also show that the SCL/Lmo2/Ldb-1 complex is recruited to the enhancer in vivo. Importantly, transplant experiments demonstrate that the intronic Runx1 enhancer targets all definitive HSCs in the mouse embryo, suggesting that it functions as a crucial cis-regulatory element that integrates the Gata, Ets and SCL transcriptional networks to initiate HSC generation.
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