PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin
Reem Elagooz, Anita R Dhara, Rose M Gott, Sarah E Adams, Rachael A White, Arnab Ghosh, Shinjini Ganguly, Yuncheng Man, Amma Owusu-Ansah, Omar Y Mian, Umut A Gurkan, Anton A Komar, Mahesh Ramamoorthy, Merlin Nithya Gnanapragasam, Reem Elagooz, Anita R Dhara, Rose M Gott, Sarah E Adams, Rachael A White, Arnab Ghosh, Shinjini Ganguly, Yuncheng Man, Amma Owusu-Ansah, Omar Y Mian, Umut A Gurkan, Anton A Komar, Mahesh Ramamoorthy, Merlin Nithya Gnanapragasam
Abstract
The fetal-to-adult hemoglobin switching at about the time of birth involves a shift in expression from γ-globin to β-globin in erythroid cells. Effective re-expression of fetal γ-globin can ameliorate sickle cell anemia and β-thalassemia. Despite the physiological and clinical relevance of this switch, its posttranscriptional regulation is poorly understood. Here, we identify Pumilo 1 (PUM1), an RNA-binding protein with no previously reported functions in erythropoiesis, as a direct posttranscriptional regulator of β-globin switching. PUM1, whose expression is regulated by the erythroid master transcription factor erythroid Krüppel-like factor (EKLF/KLF1), peaks during erythroid differentiation, binds γ-globin messenger RNA (mRNA), and reduces γ-globin (HBG1) mRNA stability and translational efficiency, which culminates in reduced γ-globin protein levels. Knockdown of PUM1 leads to a robust increase in fetal hemoglobin (∼22% HbF) without affecting β-globin levels in human erythroid cells. Importantly, targeting PUM1 does not limit the progression of erythropoiesis, which provides a potentially safe and effective treatment strategy for sickle cell anemia and β-thalassemia. In support of this idea, we report elevated levels of HbF in the absence of anemia in an individual with a novel heterozygous PUM1 mutation in the RNA-binding domain (p.(His1090Profs∗16); c.3267_3270delTCAC), which suggests that PUM1-mediated posttranscriptional regulation is a critical player during human hemoglobin switching.
Conflict of interest statement
Conflict-of-interest disclosure: The authors declare no competing financial interests.
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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Source: PubMed