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 Blood, 1 November 2008, Vol. 112, No. 9, pp. 3889-3899.
Prepublished online as a Blood First Edition Paper on August 8, 2008; DOI 10.1182/blood-2008-06-161901.

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RED CELLS

The role of the polycomb complex in silencing {alpha}-globin gene expression in nonerythroid cells

David Garrick1, Marco De Gobbi1, Vasiliki Samara1, Michelle Rugless1, Michelle Holland1, Helena Ayyub1, Karen Lower1, Jackie Sloane-Stanley1, Nicki Gray1, Christoph Koch2, Ian Dunham2, and Douglas R. Higgs1

1 Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford; and 2 EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom

Although much is known about globin gene activation in erythroid cells, relatively little is known about how these genes are silenced in nonerythroid tissues. Here we show that the human {alpha}- and β-globin genes are silenced by fundamentally different mechanisms. The {alpha}-genes, which are surrounded by widely expressed genes in a gene dense region of the genome, are silenced very early in development via recruitment of the Polycomb (PcG) complex. By contrast, the β-globin genes, which lie in a relatively gene-poor chromosomal region, are not bound by this complex in nonerythroid cells. The PcG complex seems to be recruited to the {alpha}-cluster by sequences within the CpG islands associated with their promoters; the β-globin promoters do not lie within such islands. Chromatin associated with the {alpha}-globin cluster is modified by histone methylation (H3K27me3), and silencing in vivo is mediated by the localized activity of histone deacetylases (HDACs). The repressive (PcG/HDAC) machinery is removed as hematopoietic progenitors differentiate to form erythroid cells. The {alpha}- and β-globin genes thus illustrate important, contrasting mechanisms by which cell-specific hematopoietic genes (and tissue-specific genes in general) may be silenced.


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