title: The role of the polycomb complex in silencing alpha-globin gene expression in nonerythroid cells.
abstract: 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 beta-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 beta-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 beta-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 beta-globin genes thus illustrate important, contrasting mechanisms by which cell-specific hematopoietic genes (and tissue-specific genes in general) may be silenced.
authors.affiliation: Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.
authors.forename: David
authors.initials: D
authors.lastname: Garrick
authors.forename: Marco
authors.initials: M
authors.lastname: De Gobbi
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Samara
authors.forename: Michelle
authors.initials: M
authors.lastname: Rugless
authors.forename: Michelle
authors.initials: M
authors.lastname: Holland
authors.forename: Helena
authors.initials: H
authors.lastname: Ayyub
authors.forename: Karen
authors.initials: K
authors.lastname: Lower
authors.forename: Jackie
authors.initials: J
authors.lastname: Sloane-Stanley
authors.forename: Nicki
authors.initials: N
authors.lastname: Gray
authors.forename: Christoph
authors.initials: C
authors.lastname: Koch
authors.forename: Ian
authors.initials: I
authors.lastname: Dunham
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D020868:Gene Silencing; D005914:Globins / Q000235:genetics*; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D039904:Pluripotent Stem Cells / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D063146:Polycomb-Group Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D014157:Transcription Factors; D005914:Globins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D006655:Histone Deacetylases