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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)6016-6022
Number of pages7
JournalBlood advances
Volume6
Issue number23
DOIs
StatePublished - 13 Dec 2022
Externally publishedYes

Fingerprint

Dive into the research topics of 'PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin'. Together they form a unique fingerprint.

Cite this