Expression of alpha- and beta-globin genes occurs within different nucleardomains 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 a re produced in balanced amounts, and that expression is tissue-restricted a nd specific to developmental stages. Here we compare the subnuclear locatio n 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 tha t are discrete from alpha -satellite-rich constitutive heterochromatin. How ever, in cycling lymphocytes, which do not express globin genes, the distri bution of alpha- and beta -globin genes was markedly different. beta -globi n 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 proportio n of cycling lymphocytes. In contrast, alpha -globin genes were not associa ted with centromeric heterochromatin in the nucleus of normal human lymphoc ytes, in lymphocytes from patients with alpha -thalassaemia lacking the reg ulatory 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 a lpha- and beta -globin gene clusters occurs in different nuclear environmen ts in primary haemopoietic cells.