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Human Molecular Genetics Advance Access originally published online on January 13, 2005
Human Molecular Genetics 2005 14(5):595-601; doi:10.1093/hmg/ddi056
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Human Molecular Genetics, Vol. 14, No. 5 © Oxford University Press 2005; all rights reserved

Genome-wide identification of cis-regulatory sequences controlling blood and endothelial development

Ian J. Donaldson1, Michael Chapman1, Sarah Kinston1, Josette Renée Landry1, Kathy Knezevic1, Sandie Piltz1, Noel Buckley2, Anthony R. Green1 and Berthold Göttgens1,*

1Department of Haematology, Cambridge Institute for Medical Research, Cambridge University, Hills Road, Cambridge CB2 2XY, UK and 2Schools of Biochemistry and Microbiology and Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK

* To whom correspondence should be addressed. Tel: +44 1223336822; Fax: +44 1223762670; Email: bg200{at}cam.ac.uk

Received October 27, 2004; Revised December 16, 2004; Accepted January 5, 2005

The development of blood has long served as a model for mammalian cell type specification and differentiation, and yet the underlying transcriptional networks remain ill defined. Characterization of such networks will require genome-wide identification of cis-regulatory sequences and an understanding of how regulatory information is encoded in the primary DNA sequence. Despite progress in lower organisms, genome-wide computational identification of mammalian cis-regulatory sequences has been hindered by increased genomic complexity and cumbersome transgenic assays. Starting with a well-characterized blood stem cell enhancer from the SCL gene, we have developed computational tools for the identification of functionally related gene regulatory sequences. Two candidate enhancers discovered in this way were located in intron 1 of the Fli-1 and PRH/Hex genes, both transcription factors previously implicated in controlling blood and endothelial development. Subsequent transgenic and biochemical analysis demonstrated that the two computationally identified enhancers are functionally related to the SCL stem cell enhancer. The approach developed here may therefore be useful for identifying additional enhancers involved in the control of early blood and endothelial development, and may be adapted to decipher transcriptional regulatory codes controlling a broad range of mammalian developmental programmes.


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