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|Type:||Artigo de Periódico|
|Title:||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|
|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.|
Sickle Cell Disease
|Editor:||SAGE PUBLICATIONS LTD|
|Citation:||Experimental Biology And Medicine. SAGE PUBLICATIONS LTD, n. 241, n. 7, p. 697 - 705.|
|Appears in Collections:||Unicamp - Artigos e Outros Documentos|
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