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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5456-5465.
Prepublished online as a Blood First Edition Paper on April 3, 2009; DOI 10.1182/blood-2009-01-200048.
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Submitted January 16, 2009
Accepted March 26, 2009
The transcriptional programme controlled by the stem cell leukaemia gene Scl/Tal1 during early embryonic haematopoietic development
Nicola K. Wilson, Diego Miranda-Saavedra, Sarah Kinston, Nicolas Bonadies, Samuel D. Foster, Fernando Calero-Nieto, Mark A. Dawson, Ian J. Donaldson, Stephanie Dumon, Jonathan Frampton, Rekin's Janky, Xiao-Hong Sun, Sarah A. Teichmann, Andrew J. Bannister, and Berthold Gottgens*
University of Cambridge Department of Haematology, Cambridge Institute for Medical Research, Cambridge, United Kingdom
Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom
Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, United Kingdom
MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
Oklahoma Medical Research Foundation, University of Oklahoma, Oklahoma, United States
Wellcome Trust/Cancer Research United Kingdom Gurdon Institute and Department of Pathology, Cambridge, United Kingdom
* Corresponding author; email: bg200{at}cam.ac.uk.
The basic-helix-loop-helix transcription factor Scl/Tal1 controls the development and subsequent differentiation of haematopoietic stem cells (HSCs). However, since few Scl target genes have been validated to date, the underlying mechanisms have remained largely unknown. Here we have employed ChIP-Seq technology to generate a genome-wide catalogue of Scl binding events in a stem/progenitor cell line followed by validation using primary fetal liver cells and comprehensive transgenic mouse assays. Transgenic analysis provided in vivo validation of multiple new direct Scl target genes and allowed us to reconstruct an in vivo validated network consisting of 17 factors and their respective regulatory elements. By coupling ChIP-Seq in model cell lines with in vivo transgenic validation and sophisticated bioinformatic analysis, we have identified a widely applicable strategy for the reconstruction of stem cell regulatory networks where biological material is otherwise limiting. Moreover, in addition to revealing multiple previously unrecognised links to known HSC regulators as well as novel links to genes not previously implicated in HSC function, comprehensive transgenic analysis of regulatory elements provided substantial new insights into the transcriptional control of several important haematopoietic regulators including Cbfa2t3h/Eto2, Cebpe, Nfe2, Zfpm1/Fog1, Erg, Mafk, Gfi1b and Myb.
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