title: Activation of the beta-like globin genes in transgenic mice is dependent on the presence of the beta-locus control region.
abstract: The beta-globin locus control region (LCR) is a powerful regulatory element required for high-level globin gene expression. We have generated transgenic mouse lines carrying a beta-globin locus yeast artificial chromosome lacking the LCR to determine if the LCR is required for globin gene activation. beta-Globin gene expression was analyzed by RNase protection, but no detectable levels of epsilon-, gamma- and beta-globin gene transcripts were produced at any stage of development. These findings suggest that the presence of the LCR is a minimum requirement for globin gene expression. Next, we tested whether the LCR is necessary to activate globin gene expression in a gamma-globin promoter mutant that causes hereditary persistence of fetal hemoglobin (HPFH). beta-YAC transgenic mice carrying the -117 HPFH mutation and a HS3 core deletion that specifically abolishes gamma-globin gene expression during definitive erythropoiesis were produced to test whether the -117 (A)gamma promoter is activated in the absence of interaction with the LCR. In four transgenic mouse lines, gamma-globin gene expression was absent in adult erythrocytes, suggesting that an interaction between the gamma-globin gene promoter and the LCR is required for gamma gene activation even when the promoter contains an HPFH mutation.
authors.affiliation: Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Navas
authors.forename: Qiliang
authors.initials: Q
authors.lastname: Li
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Peterson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Swank
authors.forename: Alex
authors.initials: A
authors.lastname: Rohde
authors.forename: Julianne
authors.initials: J
authors.lastname: Roy
authors.forename: George
authors.initials: G
authors.lastname: Stamatoyannopoulos
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D018244:Chromosomes, Artificial, Yeast; D005319:Fetal Hemoglobin / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D005914:Globins / Q000235:genetics*; D006801:Humans; D019901:Locus Control Region; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D015533:Transcriptional Activation
chemical_list: D012333:RNA, Messenger; D005914:Globins; D005319:Fetal Hemoglobin