The role of the polycomb complex in silencing α-globin gene expression in non-erythroid cells

Although much is known about globin gene activation in erythroid cells, relatively little is known about how these genes are silenced in non-erythroid tissues. Here we show that the human αand β-gobin genes are silenced by fundamentally different mechanisms. The α-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 non-erythroid cells. The PcG complex appears to be recruited to the α-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 α-globin cluster is modified by histone methylation (H3K27me3) and silencing in vivo is mediated by the localised activity of histone deacetylases (HDACs). The repressive (PcG/HDAC) machinery is removed as hematopoietic progenitors differentiate to form erythroid cells. The αand β-globin genes thus illustrate important, contrasting mechanisms by which cell-specific hematopoietic genes (and tissue-specific genes in general) may be silenced. 2 only. For personal use at PENN STATE UNIVERSITY on February 23, 2013. bloodjournal.hematologylibrary.org From