Independent formation of DnaseI hypersensitive sites in the murine beta-globin locus control region

Mammalian beta-globin loci are composed of multiple orthologous genes whose expression is erythroid specific and developmentally regulated. The expres sion of these genes both from the endogenous locus and from transgenes is s trongly influenced by a linked 15-kilobase region of clustered DNasel hyper sensitive sites (HSs) known as the locus control region (LCR), The LCR enco mpasses 5 major HSs, each of which is highly homologous among humans, mice, and other mammals, To analyze the function of individual HSs in the endoge nous murine beta-globin LCR, we have used homologous recombination in embry onic stem cells to produce 5 mouse lines, each of which is deficient for 1 of these major HSs. In this report, we demonstrate that deletion of the con served region of 5'HS 1,2, 3, 4, or 5/6 abolishes HS formation at the delet ion site but has no influence on the formation of the remaining HSs in the LCR. Therefore, in the endogenous murine locus, there is no dominant or ini tiating site whose formation must precede the formation of the other HSs. T his is consistent with the idea that HSs form autonomously. We discuss the implications of these findings for current models of beta-globin regulation . (Blood. 2000;95:3600-3604) (C) 2000 by The American Society of Hematology .