ArticleBlood2020
The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression.
Article in Blood, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
52 citing papers in PubMed, 71 citations in OpenAlex.
- EIF2AK1 As a Key Genetic Determinant of Luspatercept Resistance in Transfusion-Dependent Thalassemia.American journal of hematology · 2026Article
- Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.Cell metabolism · 2026Article
- New Gene Therapy Strategy for β-Thalassemia.Stem cell reviews and reports · 2026Review
- Dissecting polycomb complexes for enhanced fetal hemoglobin production.bioRxiv : the preprint server for biology · 2026Article
- LDB1 represses fetal hemoglobin expression by enhancing BCL11A transcription.Redox biology · 2026Article
- Circ_0001428 regulates erythropoiesis and γ-globin expression via activating the ATF4-BCL11A axis in β-thalassemia.Cellular and molecular life sciences : CMLS · 2026Article
- Hydroxycarbamide and Sickle Cell Anemia: Paradoxical Effects Related to Redox Mechanisms of Cellular Adaptation.ACS omega · 2025Article
- Mechanisms of Globin Gene Regulation in Mammals.Annual review of genetics · 2025Review
- Pre-established ATF4 occupancy and chromatin organization instruct selective transcription activation during integrated stress response.Nature communications · 2025Article
- Multiplex base editing of BCL11A regulatory elements to treat sickle cell disease.Cell reports. Medicine · 2025Article
- Beyond transfusions and transplants: genomic innovations rewriting the narrative of thalassemia.Annals of hematology · 2025Review
- Advancements in CRISPR/Cas systems for disease treatment.Acta pharmaceutica Sinica. B · 2025Review
- Ribosomal protein deficiencies linked to Diamond-Blackfan anemia induce distinctive alterations of ATF4 expression.iScience · 2025Article
- Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells.Cell stem cell · 2025Article
- Systematic identification and validation of ceRNA-driven regulatory mechanisms in pediatric β-Thalassemia major.Annals of hematology · 2025Article
- Review
- Transcriptional regulators of fetal hemoglobin.Hematology, transfusion and cell therapy · 2024Review
- Review
- Context matters: role of ATF4 in hematopoiesis.Blood · 2024Article
- PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease.Science advances · 2024Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and β-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kinase heme-regulated inhibitor (HRI), suggesting that HRI might present a pharmacologic target for raising fetal hemoglobin levels. Here, via a CRISPR-Cas9-guided loss-of-function screen in human erythroblasts, we identify transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin regulator. ATF4 directly stimulates transcription of BCL11A, a repressor of γ-globin transcription, by binding to its enhancer and fostering enhancer-promoter contacts. Notably, HRI-deficient mice display normal Bcl11a levels, suggesting species-selective regulation, which we explain here by demonstrating that the analogous ATF4 motif at the murine Bcl11a enhancer is largely dispensable. Our studies uncover a linear signaling pathway from HRI to ATF4 to BCL11A to γ-globin and illustrate potential limits of murine models of globin gene regulation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.