Characterization of the major regulatory element upstream of the human alpha-globin gene cluster.

Abstract

The major positive regulatory activity of the human a-globin gene complex has been localized to an element associated with a strong erythroid-specific DNase I hypersensitive site (HS -40) located 40 kb upstream of the ,2-globin mRNA cap site. Footprint and gel shift analyses of the element have demonstrated the presence of four binding sites for the nuclear factor GATA-1 and two sites corresponding to the AP-1 consensus binding sequence. This region resembles one of the major elements of the j8-globin locus control region in its constitution and characteristics; this together with evidence from expression studies suggests that HS -40 is a primary element controiling a-globin gene expression.

Analysis of the human alpha-globin gene cluster in transgenic mice.

“…A similar pattern of erythroid-specific HSs was identified 4, 8, 10, 33, and 40 kb upstream of the '2 mRNA cap site of the a gene cluster (14,15). However, only the site at -40 kb (HS -40) appeared to have a significant effect on a gene expression (14)(15)(16).…”

“…However, only the site at -40 kb (HS -40) appeared to have a significant effect on a gene expression (14)(15)(16). HS -40 contains binding sites for both erythroid restricted and ubiquitous trans-acting factors (15,17) with a pattern of protein binding closely resembling that of HS2 of the f3-LCR (15,18).…”

Novel large deletions in the human α-globin gene cluster: Clarifying the HS-40 long-range regulatory role in the native chromosome environment

“…Although the scores obtained for the delHS-40 + 39nt rearrangement were lower than those corresponding to the wild-type sequence, we acknowledge the reconstruction of the Sp1 transcription factor binding site with a similar score to that found in the normal HS-40 sequence. This Sp1 site has been reported to be essential for this element regulatory function [21][22][23]. Without further functional studies, we cannot exclude a possible long-distance regulatory role of this 39nt inserted sequence.…”

Biological, cellular, and molecular characteristics of an inducible transgenic skin tumor model: a review

“…Flanking chromosomal sequences, such as LCRs, regulate the expression of a number of genes, including the a-and b-globin genes (Tuan and London, 1984;Forrester et al, 1987;Tuan et al, 1989;Higgs et al, 1990;Jarman et al, 1991). The 5 0 regulatory sequences, such as the a-globin LCR, were not included with the z-globin promoter in the Tg.AC transgene, which may account for transgene expression in nonhematopoietic tissues (Leder et al, 1990;Delker et al, 1999).…”