dc.creator | Braghini | |
dc.creator | Carolina A.; Costa | |
dc.creator | Flavia C.; Fedosyuk | |
dc.creator | Halyna; Neades | |
dc.creator | Renee Y.; Novikova | |
dc.creator | Lesya V.; Parker | |
dc.creator | Matthew P.; Winefield | |
dc.creator | Robert D.; Peterson | |
dc.creator | Kenneth R. | |
dc.date | 2016 | |
dc.date | abr | |
dc.date | 2017-11-13T13:22:26Z | |
dc.date | 2017-11-13T13:22:26Z | |
dc.date.accessioned | 2018-03-29T05:55:11Z | |
dc.date.available | 2018-03-29T05:55:11Z | |
dc.identifier | Experimental Biology And Medicine. Sage Publications Ltd, v. 241, p. 697 - 705, 2016. | |
dc.identifier | 1535-3702 | |
dc.identifier | 1535-3699 | |
dc.identifier | WOS:000374291600004 | |
dc.identifier | 10.1177/1535370216636724 | |
dc.identifier | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871743/ | |
dc.identifier | http://repositorio.unicamp.br/jspui/handle/REPOSIP/327885 | |
dc.identifier.uri | http://repositorioslatinoamericanos.uchile.cl/handle/2250/1364910 | |
dc.description | Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) | |
dc.description | 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. | |
dc.description | 241 | |
dc.description | 7 | |
dc.description | 697 | |
dc.description | 705 | |
dc.description | National Institutes of Health [R01 HL111264, R01 DK100595, R01 DK081290] | |
dc.description | National Center for Research Resources of the National Institutes of Health [P20 RR021940] | |
dc.description | National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103549] | |
dc.description | Sao Paulo Research Foundation (FAPESP) [2014/17413-9] | |
dc.description | Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) | |
dc.language | English | |
dc.publisher | Sage Publications LTD | |
dc.publisher | London | |
dc.relation | Experimental Biology and Medicine | |
dc.rights | fechado | |
dc.source | WOS | |
dc.subject | Globin Gene | |
dc.subject | Sickle Cell Disease | |
dc.subject | Hemoglobinopathies | |
dc.subject | Hpfh | |
dc.subject | Fetal Hemoglobin | |
dc.subject | Transgenic Mice | |
dc.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 | |
dc.type | Artículos de revistas | |