Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
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]
Total Authors: 8
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
Total Affiliations: 5
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 Opportunities: Scholarships abroad - Research Internship - Doctorate