Sequences located 3' to the breakpoint of the hereditary persistence of fetal hemoglobin-3 deletion exhibit enhancer activity and can modify the developmental expression of the human fetal A gamma-globin gene in transgenic mice.

The Journal of Biological Chemistry
Nicholas P AnagnouGeorge Stamatoyannopoulos

Abstract

Expression of fetal gamma-globin genes in individuals with the deletion forms of hereditary persistence of fetal hemoglobin (HPFH) has been attributed either to enhancement by 3' regulatory elements juxtaposed to gamma-globin genes or to deletion of gamma-gene silencers normally residing within the beta-globin gene cluster. In the present study, we tested the hypothesis of imported enhancers downstream of beta-globin gene using the HPFH-3 deletion as a model. The abnormal bridging fragment of 13.6 kilobases (kb) containing the A gamma-gene with its flanking sequences and 6.2 kb of the juxtaposed region was microinjected into fertilized mouse eggs. Twelve transgenic mice positive for the fragment were generated. Samples from 11.5-day yolk sacs, 16-day fetal liver, and adult blood were analyzed for A gamma-mRNA using RNase protection assays. Three mice lacked A gamma expression in the yolk sac indicating non-optimal integration site. Four expressed A gamma-mRNA at the embryonic stage only, while two expressed A gamma-mRNA in both embryonic and fetal liver erythroid cells. Since the A gamma-gene with its normal flanking sequences and in the absence of the locus control region is expressed only in embryonic cells of transgenic mice...Continue Reading

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Citations

Feb 26, 2005·Experimental Hematology·George Stamatoyannopoulos
Mar 12, 2004·Molecular Phylogenetics and Evolution·Jianhua LingDorothy Tuan
Sep 2, 2011·The New England Journal of Medicine·Vijay G SankaranM A Bender
Dec 12, 2012·Nucleic Acids Research·Michael M HoffmanWilliam Stafford Noble
Jul 21, 1998·Annals of the New York Academy of Sciences·B G Forget
May 25, 2006·International Journal of Hematology·Khaimuk ChangsriSuthat Fucharoen
Nov 8, 2005·Molecular Diagnosis : a Journal Devoted to the Understanding of Human Disease Through the Clinical Application of Molecular Biology·Urvashi Bhardwaj, Edward R B McCabe
Dec 4, 2013·Critical Reviews in Clinical Laboratory Sciences·Ho-Wan Ip, Chi-Chiu So
Oct 13, 2006·American Journal of Hematology·Saovaros SvastiSuthat Fucharoen

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