Original Research: Generation of non-deletional hereditary persistence of fetal hemoglobin β-globin locus yeast artificial chromosome transgenic mouse models: -175 Black HPFH and -195 Brazilian HPFH.

Autor:	Braghini CA; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160 USA Hematology and Hemotherapy Center, University of Campinas, Sao Paulo, SP 13083, Brazil., Costa FC; IntelligeneDX, Olathe, KS 66061, USA., Fedosyuk H; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160 USA., Neades RY; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160 USA., Novikova LV; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160 USA., Parker MP; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160 USA., Winefield RD; Analytical Core Laboratory, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA., Peterson KR; Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160 USA Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160 USA kpeterson@kumc.edu.
Jazyk:	angličtina
Zdroj:	Experimental biology and medicine (Maywood, N.J.) [Exp Biol Med (Maywood)] 2016 Apr; Vol. 241 (7), pp. 697-705. Date of Electronic Publication: 2016 Mar 04.
DOI:	10.1177/1535370216636724
Abstrakt:	Fetal hemoglobin is a major genetic modifier of the phenotypic heterogeneity in patients with sickle cell disease and certain β-thalassemias. Normal levels of fetal hemoglobin postnatally are approximately 1% of total hemoglobin. Patients who have hereditary persistence of fetal hemoglobin, characterized by elevated synthesis of γ-globin in adulthood, show reduced disease pathophysiology. Hereditary persistence of fetal hemoglobin is caused by β-globin locus deletions (deletional hereditary persistence of fetal hemoglobin) or γ-globin gene promoter point mutations (non-deletional hereditary persistence of fetal hemoglobin). Current research has focused on elucidating the pathways involved in the maintenance/reactivation of γ-globin in adult life. To better understand these pathways, we generated new β-globin locus yeast artificial chromosome transgenic mice bearing the (A)γ-globin -175 T > C or -195 C > G hereditary persistence of fetal hemoglobin mutations to model naturally occurring hereditary persistence of fetal hemoglobin. Adult -175 and -195 mutant β-YAC mice displayed a hereditary persistence of fetal hemoglobin phenotype, as measured at the mRNA and protein levels. The molecular basis for these phenotypes was examined by chromatin immunoprecipitation of transcription factor/co-factor binding, including YY1, PAX1, TAL1, LMO2, and LDB1. In -175 HPFH versus wild-type samples, the occupancy of LMO2, TAL1 and LDB1 proteins was enriched in HPFH mice (5.8-fold, 5.2-fold and 2.7-fold, respectively), a result that concurs with a recent study in cell lines showing that these proteins form a complex with GATA-1 to mediate long-range interactions between the locus control region and the (A)γ-globin gene. Both hereditary persistence of fetal hemoglobin mutations result in a gain of (A)γ-globin activation, in contrast to other hereditary persistence of fetal hemoglobin mutations that result in a loss of repression. The mice provide additional tools to study γ-globin gene expression and may reveal new targets for selectively activating fetal hemoglobin. (© 2016 by the Society for Experimental Biology and Medicine.)
Databáze:	MEDLINE
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