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

Author(s)

Braghini, Carolina A. ^{[1, 2]} ; Costa, Flavia C. ^[3] ; Fedosyuk, Halyna ^[1] ; Neades, Renee Y. ^[1] ; Novikova, Lesya V. ^[1] ; Parker, Matthew P. ^[1] ; Winefield, Robert D. ^[4] ; Peterson, Kenneth R. ^{[1, 5]}

Affiliation

^[1] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, 3901 Rainbow Blvd, Kansas City, KS 66160 - USA

^[2] Univ Estadual Campinas, Hematol & Hemotherapy Ctr, BR-13083 Sao Paulo, SP - Brazil

^[3] IntelligeneDX, Olathe, KS 66061 - USA

^[4] Univ Kansas, Dept Pharmacol Toxicol & Therapeut, Analyt Core Lab, Med Ctr, Kansas City, KS 66160 - USA

^[5] Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Kansas City, KS 66160 - USA

• Document type: Journal article
• Source: Experimental Biology and Medicine; v. 241, n. 7, p. 697-705, APR 2016.
• Web of Science Citations: 3

Abstract

Fetal hemoglobin is a major genetic modifier of the phenotypic heterogeneity in patients with sickle cell disease and certain beta-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 gamma-globin in adulthood, show reduced disease pathophysiology. Hereditary persistence of fetal hemoglobin is caused by beta-globin locus deletions (deletional hereditary persistence of fetal hemoglobin) or gamma-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 gamma-globin in adult life. To better understand these pathways, we generated new beta-globin locus yeast artificial chromosome transgenic mice bearing the (A)gamma-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 b-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)gamma-globin gene. Both hereditary persistence of fetal hemoglobin mutations result in a gain of (A)gamma-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 gamma-globin gene expression and may reveal new targets for selectively activating fetal hemoglobin. (AU)

• FAPESP's process: 14/17413-9 - Investigation of transcription factors involved in HBG1 gene expression regulation employing transgenic beta-YAC mice and CD34+ human cells models with Brazilian type of non-deletional hereditary persistence of fetal hemoglobin
• Grantee: Carolina Ayumi Braghini
• Support type: Scholarships abroad - Research Internship - Doctorate