ArticlePLoS genetics2015
A Systems Approach Identifies Essential FOXO3 Functions at Key Steps of Terminal Erythropoiesis.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 72 citations in OpenAlex.
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- Bnip3lb-driven mitophagy maintains fate of the embryonic hematopoietic stem cell pool.Nature communications · 2026Article
- Global comprehensive transcriptomic and proteomic analyses of murine terminal erythroid differentiation.Global medical genetics · 2025Article
- New insights into the mechanisms of red blood cell enucleation: From basics to clinical applications.EJHaem · 2024Review
- Erythroblast enucleation at a glance.Journal of cell science · 2024Review
- Enhancing terminal erythroid differentiation in human embryonic stem cells through TRIB3 overexpression.Heliyon · 2024Article
- Mitochondrial regulation of erythropoiesis in homeostasis and disease.British journal of haematology · 2024Review
- Human red blood cells express the RNA sensor TLR7.Scientific reports · 2024Article
- Decoding human in vitro terminal erythropoiesis originating from umbilical cord blood mononuclear cells and pluripotent stem cells.Cell proliferation · 2024Article
- Entire expressed peripheral blood transcriptome in pediatric severe malarial anemia.Nature communications · 2024Article
- Modeling primitive and definitive erythropoiesis with induced pluripotent stem cells.Blood advances · 2024Article
- Metformin as a Fetal Hemoglobin Inducer in Non-transfusion Dependent Thalassemia Patients.Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion · 2024Article
- Comprehensive Characterization and Global Transcriptome Analysis of Human Fetal Liver Terminal Erythropoiesis.Genomics, proteomics & bioinformatics · 2023Article
- Elevated CDKN1A (P21) mediates β-thalassemia erythroid apoptosis, but its loss does not improve β-thalassemic erythropoiesis.Blood advances · 2023Article
- Nucleolar Protein 56 Deficiency in Zebrafish Leads to Developmental Abnormalities and Anemia viaBiology · 2023Article
- Nucleated red blood cells explain most of the association between DNA methylation and gestational age.Communications biology · 2023Article
- The accumulation of miR-125b-5p is indispensable for efficient erythroblast enucleation.Cell death & disease · 2022Article
- Article
- Analyses of erythropoiesis from embryonic stem cell-CD34Journal of cellular and molecular medicine · 2022Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
Circulating red blood cells (RBCs) are essential for tissue oxygenation and homeostasis. Defective terminal erythropoiesis contributes to decreased generation of RBCs in many disorders. Specifically, ineffective nuclear expulsion (enucleation) during terminal maturation is an obstacle to therapeutic RBC production in vitro. To obtain mechanistic insights into terminal erythropoiesis we focused on FOXO3, a transcription factor implicated in erythroid disorders. Using an integrated computational and experimental systems biology approach, we show that FOXO3 is essential for the correct temporal gene expression during terminal erythropoiesis. We demonstrate that the FOXO3-dependent genetic network has critical physiological functions at key steps of terminal erythropoiesis including enucleation and mitochondrial clearance processes. FOXO3 loss deregulated transcription of genes implicated in cell polarity, nucleosome assembly and DNA packaging-related processes and compromised erythroid enucleation. Using high-resolution confocal microscopy and imaging flow cytometry we show that cell polarization is impaired leading to multilobulated Foxo3-/- erythroblasts defective in nuclear expulsion. Ectopic FOXO3 expression rescued Foxo3-/- erythroblast enucleation-related gene transcription, enucleation defects and terminal maturation. Remarkably, FOXO3 ectopic expression increased wild type erythroblast maturation and enucleation suggesting that enhancing FOXO3 activity may improve RBCs production. Altogether these studies uncover FOXO3 as a novel regulator of erythroblast enucleation and terminal maturation suggesting FOXO3 modulation might be therapeutic in disorders with defective erythroid maturation.
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