Human gamma- to beta-globin gene switching in transgenic mice.
Previous studies demonstrated correct tissue- and temporal-specific expression of human gamma- and beta-globin genes in transgenic mice; however, expression was extremely low. When the erythroid-specific DNase I super-hypersensitive (HS) sites that are normally located upstream of the human beta-globin locus were fused individually to gamma- or beta-globin genes, expression increased to endogenous mouse globin levels but temporal specificity was lost. In contrast, when the HS sequences were combined with fragments containing both gamma- and beta-globin genes, correct developmental regulation was restored. We suggest that human gamma- to beta-globin gene switching during development results from competition of individual globin gene family members for interaction with the HS sequences and that factors influencing these competitive interactions determine temporal specificity.
Behringer
R R
RR
Laboratory of Reproductive Physiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104.
Ryan
T M
TM
Palmiter
R D
RD
Brinster
R L
RL
Townes
T M
TM
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D003850:Deoxyribonuclease I / Q000378:metabolism*; D004912:Erythrocytes / Q000378:metabolism; D005786:Gene Expression Regulation; D005809:Genes, Regulator; D005812:Genes, Switch; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012313:RNA / Q000032:analysis
D012313:RNA; D005914:Globins; D004247:DNA; D003850:Deoxyribonuclease I