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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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Autor(es):
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]
Número total de Autores: 8
Afiliação do(s) autor(es):
[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
Número total de Afiliações: 5
Tipo de documento: Artigo Científico
Fonte: Experimental Biology and Medicine; v. 241, n. 7, p. 697-705, APR 2016.
Citações Web of Science: 3
Resumo

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)

Processo FAPESP: 14/17413-9 - Investigação dos fatores de transcrição envolvidos na regulação da expressão do gene HBG1 usando modelos de camundongos beta-YAC e células humanas CD34+ com persistência hereditária de hemoglobina fetal não delecional tipo brasileira
Beneficiário:Carolina Ayumi Braghini
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Doutorado