RED CELLS Deletion of the core region of 5 HS2 of the mouse -globin locus control region reveals a distinct effect in comparison with human -globin transgenes

The -globin locus control region (LCR) is a large DNA element that is required for high-level expression of -like globin genes from the endogenous mouse locus or in transgenic mice carrying the human -globin locus. The LCR encompasses 6 DNaseI hypersensitive sites (HSs) that bind transcription factors. These HSs each contain a core of a few hundred base pairs (bp) that has most of the functional activity and exhibits high interspecies sequence homology. Adjoining the cores are 500to 1000-bp “flanks” with weaker functional activity and lower interspecies homology. Studies of human -globin transgenes and of the endogenous murine locus show that deletion of an entire HS (core plus flanks) moderately suppresses expression. However, human transgenes in which only individual HS core regions were deleted showed drastic loss of expression accompanied by changes in chromatin structure. To address these disparate results, we have deleted the core region of 5 HS2 from the endogenous murine -LCR. The phenotype was similar to that of the larger 5 HS2 deletion, with no apparent disruption of chromatin structure. These results demonstrate that the greater severity of HS core deletions in comparison to full HS deletions is not a general property of the -LCR. (Blood. 2006;107:821-826)