PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin

• DOI: 10.1182/bloodadvances.2021006730
• Publication Date: 2022-06-06T21:22:30Z
• Authors: 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 Gna...
• Keywords: Adult; 0303 health sciences; 03 medical and health sciences; beta-Thalassemia; Humans; RNA-Binding Proteins; gamma-Globins; beta-Globins; Anemia, Sickle Cell; Carrier Proteins; Stimulus Report; Fetal Hemoglobin

The fetal-to-adult hemoglobin switching at about the time of birth involves a shift in expression from γ-globin to β-globin erythroid cells. Effective re-expression fetal can ameliorate sickle cell anemia and β-thalassemia. Despite physiological clinical relevance this switch, its posttranscriptional regulation is poorly understood. Here, we identify Pumilo 1 (PUM1), an RNA-binding protein with no previously reported functions erythropoiesis, as direct regulator switching. PUM1, whose regulated by master transcription factor Krüppel-like (EKLF/KLF1), peaks during differentiation, binds messenger RNA (mRNA), reduces (HBG1) mRNA stability translational efficiency, which culminates reduced levels. Knockdown PUM1 leads robust increase (∼22% HbF) without affecting levels human Importantly, targeting does not limit progression provides potentially safe effective treatment strategy for In support idea, report elevated HbF absence individual novel heterozygous mutation domain (p.(His1090Profs∗16); c.3267_3270delTCAC), suggests that PUM1-mediated critical player