Functional Analysis of an γ-Globin Gene Promoter Variant ( HBG1 : g.-225_-222delAGCA) Underlines Its Role in Increasing Fetal Hemoglobin Levels Under Erythropoietic Stress.

Autor:	Ugrin, Milena, Stojiljkovic, Maja, Zukic, Branka, Klaassen, Kristel, Katsila, Theodora, Vasiljevic, Jovana, Dokmanovic, Lidija, Janic, Dragana, Patrinos, George P., Pavlovic, Sonja
Předmět:	IRON in the blood HEMOGLOBINS HEMOGLOBIN polymorphisms BLOOD proteins FETAL hemoglobin ERYTHROPOIETIC failure
Zdroj:	Hemoglobin; Jan2016, Vol. 40 Issue 1, p48-52, 5p
Abstrakt:	Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by persistent γ-globin gene expression and synthesis of high levels of fetal hemoglobin (Hb F; α2γ2) during adult life. It is usually caused by promoter variants or large deletions affecting the human fetal globin (HBG1andHBG2) genes. Some of these HPFH-causing variants, such asHBG2: g.-158 C > T, exert their effect only under conditions of erythropoietic stress, typical for β-thalassemia (β-thal) patients. Namely, the presence ofHBG2: g.-158 C > T favors a higher Hb F response, while it has little effect in healthy individuals. We analyzed a previously reported deletion residing in the promoter region of theHBG1gene (HBG1: g.-225_-222delAGCA), both in normal conditions and under conditions of erythropoietic stress. Our results indicate that this deletion is responsible for decreasedHBG1gene expression. Specifically, this deletion was shown to result in drastically reduced reporter gene expression in K562 cells, compared to the wild-type sequence but only under conditions of erythropoietic stress, mimicked by introduction of erythropoietin (EPO) into the cell culture. Also, electrophoretic mobility shift analysis showed that theHBG1: g.-225_-222delAGCA deletion creates additional transcriptional factors’ binding sites, which, we propose, bind a transcriptional repressor, thus decreasing theHBG1gene promoter activity. These results are consistent within silicoanalysis, which indicated that this deletion creates a binding site for GATA1, known to be a repressor of the γ-globin gene expression. These data confirm the regulatory role of theHBG1: g.-225_-222 region that exerts its effect under conditions of erythropoietic stress characteristic for β-thal patients. [ABSTRACT FROM PUBLISHER]
Databáze:	Complementary Index
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