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 Blood, 5 November 2009, Vol. 114, No. 19, pp. 4253-4260.
Prepublished online as a Blood First Edition Paper on August 20, 2009; DOI 10.1182/blood-2009-03-213439.

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RED CELLS, IRON, AND ERYTHROPOIESIS

Chromosome looping at the human {alpha}-globin locus is mediated via the major upstream regulatory element (HS –40)

Douglas Vernimmen1, Fatima Marques-Kranc1, Jacqueline A. Sharpe1, Jacqueline A. Sloane-Stanley1, William G. Wood1, Helen A. C. Wallace2, Andrew J. H. Smith2, and Douglas R. Higgs1

1 Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford; and 2 Institute for Stem Cell Research, University of Edinburgh, Edinburgh, United Kingdom

Previous studies in the mouse have shown that high levels of {alpha}-globin gene expression in late erythropoiesis depend on long-range, physical interactions between remote upstream regulatory elements and the globin promoters. Using quantitative chromosome conformation capture (q3C), we have now analyzed all interactions between 4 such elements lying 10 to 50 kb upstream of the human {alpha} cluster and their interactions with the {alpha}-globin promoter. All of these elements interact with the {alpha}-globin gene in an erythroid-specific manner. These results were confirmed in a mouse model of human {alpha} globin expression in which the human cluster replaces the mouse cluster in situ (humanized mouse). We have also shown that expression and all of the long-range interactions depend largely on just one of these elements; removal of the previously characterized major regulatory element (called HS –40) results in loss of all the interactions and {alpha}-globin expression. Reinsertion of this element at an ectopic location restores both expression and the intralocus interactions. In contrast to other more complex systems involving multiple upstream elements and promoters, analysis of the human {alpha}-globin cluster during erythropoiesis provides a simple and tractable model to understand the mechanisms underlying long-range gene regulation.


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