Expression of α- and β-globin genes occurs within different nuclear domains in haemopoietic cells

The alpha- and beta -globin gene clusters have been extensively studied(1-3). Regulation of these genes ensures that proteins derived from both loci are produced in balanced amounts, and that expression is tissue-restricted and specific to developmental stages. Here we compare the subnuclear location of the endogenous alpha- and beta -globin loci in primary human cells in which the genes are either actively expressed or silent. In erythroblasts, the alpha- and beta -globin genes are localized in areas of the nucleus that are discrete from alpha -satellite-rich constitutive heterochromatin. However, in cycling lymphocytes, which do not express globin genes, the distribution of alpha- and beta -globin genes was markedly different. beta -globin loci, in common with several inactive genes studied here (human c-fms and SOX-1) and previously (mouse lambda5, CD4, CD8 alpha, RAGs, TdT and Sox-1)(4,5), were associated with pericentric heterochromatin in a high proportion of cycling lymphocytes. In contrast, alpha -globin genes were not associated with centromeric heterochromatin in the nucleus of normal human lymphocytes, in lymphocytes from patients with alpha -thalassaemia lacking the regulatory HS-40 element or entire upstream region of the alpha -globin locus, or in mouse erythroblasts and lymphocytes derived from human alpha -globin transgenic mice. These data show that the normal regulated expression of alpha- and beta -globin gene clusters occurs in different nuclear environments in primary haemopoietic cells.