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Blood, 4 June 2009, Vol. 113, No. 23, pp. 5783-5792. Prepublished online as a Blood First Edition Paper on January 26, 2009; DOI 10.1182/blood-2008-11-187757. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-11-187757v1 113/23/5783    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Landry, J.-R. Articles by Gottgens, B. Search for Related Content PubMed PubMed Citation Articles by Landry, J.-R. Articles by Gottgens, B. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 4, 2008 Accepted January 16, 2009 Expression of the leukaemia oncogene Lmo2 is controlled by an array of tissue specific elements dispersed over 100kb and bound by Tal1/Lmo2, Ets and Gata factors Josette-Renee Landry, Nicolas Bonadies, Sarah Kinston, Kathy Knezevic, Nicola K. Wilson, S. Helen Oram, Mary Janes, Sandie Piltz, Michelle Hammett, Jacinta Carter, Tina Hamilton, Ian J. Donaldson, Georges Lacaud, Jonathan Frampton, George Follows, Valerie Kouskoff, and Berthold Gottgens* Department of Haematology, Cambridge Institute for Medical Research, Cambridge University, Cambridge, United Kingdom Paterson Institute for Cancer Research, Christie Hospital, Manchester, United Kingdom Institute of Biomedical Research, The Medical School, University of Birmingham, Birmingham, United Kingdom * Corresponding author; email: bg200{at}cam.ac.uk. The Lmo2 gene encodes a transcriptional cofactor critical for the development of haematopoietic stem cells. Ectopic LMO2 expression causes T-cell leukaemia in T-ALL patients and SCID patients undergoing retroviral gene therapy. Tightly controlled Lmo2 expression is therefore essential, yet no comprehensive analysis of Lmo2 regulation has been published so far. By comparative genomics we identified 17 highly conserved non-coding elements, nine of which revealed specific acetylation marks in ChIP-chip assays performed across 250kb of the Lmo2 locus in 11 cell types covering different stages of haematopoietic differentiation. All candidate regulatory regions were tested in transgenic mice. An extended LMO2 proximal promoter fragment displayed strong endothelial activity, while the distal promoter showed weak forebrain activity. Eight of the 15 distal candidate elements functioned as enhancers which together recapitulated the full expression pattern of Lmo2, directing expression to endothelium, haematopoietic cells, tail and forebrain. Interestingly, distinct combinations of specific distal regulatory elements were required to extend endothelial activity of the LMO2 promoter to yolk sac or fetal liver haematopoietic cells. Finally, Sfpi1/Pu.1, Fli1, Gata2, Tal1/Scl and Lmo2 were shown to bind to and transactivate Lmo2 haematopoietic enhancers thus identifying key upstream regulators and positioning Lmo2 within haematopoietic regulatory networks. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: It takes (LMO) 2 to tango Ross C. Hardison Blood 2009 113: 5693. [Full Text] [PDF] This article has been cited by other articles: R. C. Hardison It takes (LMO) 2 to tango Blood, June 4, 2009; 113(23): 5693 - 5693. [Full Text] [PDF] N. K. Wilson, D. Miranda-Saavedra, S. Kinston, N. Bonadies, S. D. Foster, F. Calero-Nieto, M. A. Dawson, I. J. Donaldson, S. Dumon, J. Frampton, et al. The transcriptional program controlled by the stem cell leukemia gene Scl/Tal1 during early embryonic hematopoietic development Blood, May 28, 2009; 113(22): 5456 - 5465. [Abstract] [Full Text] [PDF]

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