Garrick David, De Gobbi Marco, Samara Vasiliki, Rugless Michelle, Holland Michelle, Ayyub Helena, Lower Karen, Sloane-Stanley Jackie, Gray Nicki, Koch Christoph, Dunham Ian, Higgs Douglas R
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.
Blood. 2008 Nov 1;112(9):3889-99. doi: 10.1182/blood-2008-06-161901. Epub 2008 Aug 8.
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.
尽管我们对红系细胞中珠蛋白基因的激活了解颇多，但对于这些基因在非红系组织中是如何沉默的却知之甚少。在此我们表明，人类α-和β-珠蛋白基因通过根本不同的机制被沉默。α-基因在基因组的基因密集区域被广泛表达的基因所环绕，在发育早期通过多梳（PcG）复合体的募集而被沉默。相比之下，位于相对基因贫乏的染色体区域的β-珠蛋白基因，在非红系细胞中不被该复合体结合。PcG复合体似乎通过与其启动子相关的CpG岛内的序列被募集到α-基因簇；β-珠蛋白启动子并不位于此类岛内。与α-珠蛋白基因簇相关的染色质通过组蛋白甲基化（H3K27me3）被修饰，并且体内沉默由组蛋白去乙酰化酶（HDACs）的局部活性介导。随着造血祖细胞分化形成红系细胞，抑制性（PcG/HDAC）机制被去除。α-和β-珠蛋白基因因此阐明了细胞特异性造血基因（以及一般的组织特异性基因）可能被沉默的重要且形成对比的机制。
