title: Persistent gamma-globin expression in adult transgenic mice is mediated by HPFH-2, HPFH-3, and HPFH-6 breakpoint sequences.
abstract: Deletions at the 3' end of the human beta-globin locus are associated with the hereditary persistence of fetal hemoglobin (HPFH) in adults, potentially through the juxtaposition of enhancer elements in the vicinity of the fetal gamma-globin genes. We have tested how sequences at the HPFH-2, HPFH-3, and HPFH-6 breakpoints, which act as enhancers in vitro, affect the silencing of a locus control region A gamma (LCRA gamma) transgene in the adult stage of mice. We found persistent A gamma expression in the adult blood of most of the multicopy HPFH-2, HPFH-3, or HPFH-6 lines, in contrast to the control LCRA gamma lines which were silenced. Cre-mediated generation of single copy lines showed persistent gamma gene expression maintained in some of the HPFH-2 and HPFH-6 lines, but not in any of the HPFH-3 or LCRA gamma lines. In the HPFH-2 and HPFH-6 lines, persistent gamma gene expression correlated with euchromatic transgene integrations. Thus, our observations provide support for a model whereby HPFH conditions arise from the juxtaposition of enhancers as well as permissive chromatin subdomains in the vicinity of the gamma-globin genes.
authors.affiliation: Department of Basic Sciences, University of Crete School of Medicine, Heraklion, Greece.
authors.forename: Eleni Z
authors.initials: EZ
authors.lastname: Katsantoni
authors.forename: An
authors.initials: A
authors.lastname: Langeveld
authors.forename: Albert W K
authors.initials: AW
authors.lastname: Wai
authors.forename: Dubravka
authors.initials: D
authors.lastname: Drabek
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Anagnou
authors.forename: John
authors.initials: J
authors.lastname: Strouboulis
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D004742:Enhancer Elements, Genetic; D005319:Fetal Hemoglobin / Q000235:genetics*; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D005812:Genes, Switch; D005914:Globins / Q000235:genetics*; D006801:Humans; D019901:Locus Control Region / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017384:Sequence Deletion / Q000502:physiology*
chemical_list: D005914:Globins; D005319:Fetal Hemoglobin