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

dc.creatorBraghini
dc.creatorCA; Costa
dc.creatorFC; Fedosyuk
dc.creatorH; Neades
dc.creatorRY; Novikova
dc.creatorLV; Parker
dc.creatorMP; Winefield
dc.creatorRD; Peterson
dc.creatorKR
dc.date2016
dc.date2016-12-06T18:31:40Z
dc.date2016-12-06T18:31:40Z
dc.date.accessioned2018-03-29T02:04:16Z
dc.date.available2018-03-29T02:04:16Z
dc.identifier1535-3699
dc.identifierExperimental Biology And Medicine. SAGE PUBLICATIONS LTD, n. 241, n. 7, p. 697 - 705.
dc.identifier1535-3702
dc.identifierWOS:000374291600004
dc.identifier10.1177/1535370216636724
dc.identifierhttp://ebm.sagepub.com/content/early/2016/03/04/1535370216636724
dc.identifierhttp://repositorio.unicamp.br/jspui/handle/REPOSIP/320347
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/1311113
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.descriptionFetal 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.
dc.description241
dc.description
dc.description697
dc.description705
dc.descriptionNational Institutes of Health [R01 HL111264, R01 DK100595, R01 DK081290]
dc.descriptionNational Center for Research Resources of the National Institutes of Health [P20 RR021940]
dc.descriptionNational Institute of General Medical Sciences of the National Institutes of Health [P20 GM103549]
dc.descriptionSao Paulo Research Foundation (FAPESP) [2014/17413-9]
dc.descriptionFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description
dc.description
dc.description
dc.languageEnglish
dc.publisherSAGE PUBLICATIONS LTD
dc.publisherLONDON
dc.relationExperimental Biology and Medicine
dc.rightsfechado
dc.sourceWOS
dc.subjectGlobin Gene
dc.subjectSickle Cell Disease
dc.subjectHemoglobinopathies
dc.subjectHpfh
dc.subjectFetal Hemoglobin
dc.subjectTransgenic Mice
dc.titleGeneration Of Non-deletional Hereditary Persistence Of Fetal Hemoglobin Beta-globin Locus Yeast Artificial Chromosome Transgenic Mouse Models:-175 Black Hpfh And-195 Brazilian Hpfh
dc.typeArtículos de revistas


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