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PUM1 mediates the posttranscriptional regulation of human 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 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 swit...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society of Hematology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699939/ https://www.ncbi.nlm.nih.gov/pubmed/35667093 http://dx.doi.org/10.1182/bloodadvances.2021006730 |
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author | Elagooz, Reem Dhara, Anita R. Gott, Rose M. Adams, Sarah E. White, Rachael A. Ghosh, Arnab Ganguly, Shinjini Man, Yuncheng Owusu-Ansah, Amma Mian, Omar Y. Gurkan, Umut A. Komar, Anton A. Ramamoorthy, Mahesh Gnanapragasam, Merlin Nithya |
author_facet | Elagooz, Reem Dhara, Anita R. Gott, Rose M. Adams, Sarah E. White, Rachael A. Ghosh, Arnab Ganguly, Shinjini Man, Yuncheng Owusu-Ansah, Amma Mian, Omar Y. Gurkan, Umut A. Komar, Anton A. Ramamoorthy, Mahesh Gnanapragasam, Merlin Nithya |
author_sort | Elagooz, Reem |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9699939 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | The American Society of Hematology |
record_format | MEDLINE/PubMed |
spelling | pubmed-96999392022-11-30 PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin Elagooz, Reem Dhara, Anita R. Gott, Rose M. Adams, Sarah E. White, Rachael A. Ghosh, Arnab Ganguly, Shinjini Man, Yuncheng Owusu-Ansah, Amma Mian, Omar Y. Gurkan, Umut A. Komar, Anton A. Ramamoorthy, Mahesh Gnanapragasam, Merlin Nithya Blood Adv Stimulus Report 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. The American Society of Hematology 2022-06-08 /pmc/articles/PMC9699939/ /pubmed/35667093 http://dx.doi.org/10.1182/bloodadvances.2021006730 Text en © 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. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Stimulus Report Elagooz, Reem Dhara, Anita R. Gott, Rose M. Adams, Sarah E. White, Rachael A. Ghosh, Arnab Ganguly, Shinjini Man, Yuncheng Owusu-Ansah, Amma Mian, Omar Y. Gurkan, Umut A. Komar, Anton A. Ramamoorthy, Mahesh Gnanapragasam, Merlin Nithya PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin |
title | PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin |
title_full | PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin |
title_fullStr | PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin |
title_full_unstemmed | PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin |
title_short | PUM1 mediates the posttranscriptional regulation of human fetal hemoglobin |
title_sort | pum1 mediates the posttranscriptional regulation of human fetal hemoglobin |
topic | Stimulus Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9699939/ https://www.ncbi.nlm.nih.gov/pubmed/35667093 http://dx.doi.org/10.1182/bloodadvances.2021006730 |
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