Article ; Online: PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin.
2022 Volume 6, Issue 23, Page(s) 6016–6022
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 ... ...
| 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. |
|||||
|---|---|---|---|---|---|---|
| MeSH term(s) | Adult ; Humans ; Fetal Hemoglobin/genetics ; Fetal Hemoglobin/metabolism ; gamma-Globins/genetics ; gamma-Globins/metabolism ; beta-Thalassemia/genetics ; beta-Globins/genetics ; Carrier Proteins ; Anemia, Sickle Cell/genetics ; RNA-Binding Proteins/genetics | |||||
| Chemical Substances | Fetal Hemoglobin (9034-63-3) ; gamma-Globins ; beta-Globins ; Carrier Proteins ; PUM1 protein, human ; RNA-Binding Proteins | |||||
| Language | English | |||||
| Publishing date | 2022-06-10 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural | |||||
| ZDB-ID | 2915908-8 | |||||
| ISSN | 2473-9537 ; 2473-9529 | |||||
| ISSN (online) | 2473-9537 | |||||
| ISSN | 2473-9529 | |||||
| DOI | 10.1182/bloodadvances.2021006730 | |||||
| Shelf mark |
|
|||||
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 7153: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.