Iron and Heme Coordinate Erythropoiesis through HRI-Mediated Regulation of Protein Translation and Gene Expression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA488955 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7777900.fastq.gz | Fastqsanger.gz | |||
| SRR7777910.fastq.gz | Fastqsanger.gz | |||
| SRR7777901.fastq.gz | Fastqsanger.gz | |||
| SRR7777911.fastq.gz | Fastqsanger.gz | |||
| SRR7777902.fastq.gz | Fastqsanger.gz |
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Project description:Iron and heme play central roles in red blood cell production. However, the mechanisms by which iron and heme levels coordinate erythropoiesis remain incompletely understood. HRI is a heme-regulated kinase that controls translation by phosphorylating eIF2a. Here, we investigate the global impact of iron, heme and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. By defining the underlying changes in translation during iron and HRI deficiencies, we validate known regulators of this process, including Atf4, and identify novel pathways such as co-regulation of ribosomal protein mRNA translation. Surprisingly, we found that heme and HRI pathways, but not iron-regulated pathways, mediate the major protein translational and transcriptional responses to iron deficiency in erythroblasts in vivo and thereby identify previously unappreciated regulators of erythropoiesis. Our genome-wide study uncovers the major impact of the HRI-mediated integrated stress response for the adaptation to iron deficiency anemia.
2018-09-03 | GSE119365 | GEO
Project description:Heme-regulated inhibitorRegulated Inhibitor (HRI) is one of the four mammalian kinases that phosphorylate eIF2α, facilitating a cellular response to stress through the regulation of mRNA translation. Originally identified as a heme sensor in erythroid progenitor cells, HRI has since emerged as a potential therapeutic target in both cancer and neurodegeneration. Here we purified recombinant expressed human HRI and allowed it to autophosphorylate.
2025-06-18 | PXD064940 | Pride
Project description:Heme-regulated eIF2α kinase (HRI) is essential for the survival of erythroid precursors in iron and heme deficiency and it also plays a protective role in red blood cell diseases of erythroid protoporphyria and β-thalassemia. In this study, we demonstrated for the first time the impairment of GATA-1 and Fog-1 expressions in iron deficiency and the impairment of GATA-1 expression in β-thalassemia. Furthermore, HRI is necessary to maintain the GATA-1/Fog-1 induced functions in erythroid differentiation, cell cycle and cell survival by sustaining both expressions of GATA-1 and Fog-1 in iron deficiency and in β-thalassemia. Keywords: Genetic modification
2009-06-30 | GSE6808 | GEO
Project description:Protective humoral responses require that B cells successfully complete their differentiation programs even when exposed to hostile environments generated during severe infections, like the massive hemolysis triggered by malaria. The mechanisms utilized by differentiating B cells to withstand damaging conditions replete in PAMPs and DAMPs are poorly understood. Here we demonstrate that the serine-threonine kinase ROCK1 enables B cells to execute their differentiation programs upon exposure to PAMPs and high levels of heme, a critical DAMP, by controlling two key heme-regulated molecules, Bach2 and HRI. ROCK1 restrains plasma cell differentiation by phosphorylating Bach2. As B cells differentiate in the presence of PAMPs and heme, furthermore, ROCK1 limits the proinflammatory potential of B cells and restrains mTORC1 activity by controlling the assembly of multimolecular complexes that contain the adaptor p62, raptor, ripoptosome components, and molecules involved in RNA metabolism and proteostasis. ROCK1 regulates formation of these complexes by controlling the interplay between HSPs and the stress kinase HRI. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity and localization of key molecules that mediate cell-fate decisions, effector functions, and RNA and protein homeostasis. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses and these findings may be broadly relevant for infections, vaccine development, and immune-mediated diseases marked by chronic tissue damage like autoimmune disorders.
2025-04-02 | GSE237201 | GEO
Project description:Erythropoietic homeostasis is coordinated by erythroblast development and challenged by a number of genetic diseases including polycythemia vera. Erythroblasts and central macrophages form erythroblastic islands to provide a specific environment for erythropoiesis. However, how central macrophages interplay with erythroblasts during erythropoiesis remains to be further clarified. In this study, we found that erythroid-specific TFPI knockout decreased the number of erythroblasts under both steady-state and stress conditions, and the function of TFPI in erythropoiesis was mediated by macrophages. TFPI affects the downstream heme synthesis pathway of central macrophages, as shown by RNA sequencing analysis, and the deletion of TFPI reduced the heme content of macrophages by inhibiting ferrochelatase (Fech) expression. Our results show that TFPI plays an important role in the regulation of erythropoiesis and reveal a new mechanism of interplay between erythroblasts and macrophages. TFPI will also provide a new potential treatment strategy for polycythemia vera.
2024-03-01 | GSE224994 | GEO
Project description:Iron deficiency (ID) anemia is a prevalent disease, yet molecular mechanisms by which iron and heme regulate erythropoiesis are not completely understood. Heme-regulated eIF2α kinase (HRI) is a key hemoprotein in erythroid precursors that sense intracellular heme concentrations to balance globin synthesis with the amount of heme available for hemoglobin production. HRI is activated by heme deficiency and oxidative stress, and it phosphorylates eIF2α (eIF2αP), which inhibits the translation of globin messenger RNAs (mRNAs) and selectively enhances the translation of activating transcription factor 4 (ATF4) mRNA to induce stress response genes. Here, we generated a novel mouse model (eAA) with the erythroid-specific ablation of eIF2αP and demonstrated that eIF2αP is required for induction of ATF4 protein synthesis in vivo in erythroid cells during ID. We show for the first time that both eIF2αP and ATF4 are necessary to promote erythroid differentiation and to reduce oxidative stress in vivo during ID. Furthermore, the HRI-eIF2αP-ATF4 pathway suppresses mTORC1 signaling specifically in the erythroid lineage. Pharmacologic inhibition of mTORC1 significantly increased red blood cell counts and hemoglobin content in the blood, improved erythroid differentiation, and reduced splenomegaly of iron-deficient Hri-/- and eAA mice. However, globin inclusions and elevated oxidative stress remained, demonstrating the essential nonredundant role of HRI-eIF2αP in these processes. Dietary iron repletion completely reversed ID anemia and ineffective erythropoiesis of Hri-/- , eAA, and Atf4-/- mice by inhibiting both HRI and mTORC1 signaling. Thus, HRI coordinates 2 key translation-regulation pathways, eIF2αP and mTORC1, to circumvent ineffective erythropoiesis, highlighting heme and translation in the regulation of erythropoiesis.
| S-EPMC5790126 | biostudies-literature
Project description:Increasing fetal hemoglobin (HbF) levels in adult red blood cells provides clinical benefit to patients with sickle cell disease and some forms of beta-thalassemia. To identify potentially druggable HbF regulators in adult human erythroid cells, we employed a protein kinase-domain focused CRISPR/Cas9-based genetic screen with a newly optimized sgRNA scaffold. The screen uncovered the heme-regulated inhibitor HRI (also known as EIF2AK1), an erythroid-specific kinase that controls protein translation, as an HbF repressor. HRI depletion markedly increased HbF production in a specific manner and reduced sickling in cultured erythroid cells. Diminished expression of the HbF repressor BCL11A accounted in large part for the effects of HRI depletion. Taken together, these results suggest HRI as a potential therapeutic target for hemoglobinopathies.
2018-07-20 | GSE115687 | GEO
Project description:Increasing fetal hemoglobin (HbF) provides clinical benefit in patients with sickle cell disease (SCD). We recently identified heme-regulated inhibitor (HRI, EIF2AK1) as a novel HbF regulator. Since HRI is an erythroid-specific protein kinase it presents a potential target for pharmacologic intervention. We find that maximal HbF induction requires >80-85% HRI depletion. As it remains unclear whether this degree of HRI inhibition can be achieved pharmacologically, we explored whether HRI knockdown can be combined with pharmacologic HbF inducers to achieve greater HbF production and minimize potential adverse effects associated with treatments. Strongly cooperative HbF induction was observed when HRI depletion was combined with exposure to pomalidomide or the EHMT1/2 inhibitor UNC0638, but not hydroxyurea. Mechanistically, reduction in the levels of the HbF repressor BCL11A reflected the cooperativity of HRI loss and pomalidomide treatment, whereas UNC0638 did not modulate BCL11A levels. In conjunction with HRI loss, pomalidomide maintained its HbF inducing activity at 10-fold lower concentrations, at which condition there were minimal observed detrimental effects on erythroid cell maturation and viability as well as fewer alterations in the erythroid transcriptome. In sum, this study provides a foundation for the exploration of combining future small molecule HRI inhibitors with additional pharmacologic HbF inducers to maximize HbF production and preserve erythroid cell functionality for the treatment of SCD and other hemoglobinopathies.
2020-09-21 | GSE150341 | GEO
Project description:ROCK1 orchestrates B cell differentiation in response to PAMPs and heme by controlling the heme-regulated proteins Bach2 and HRI
| PRJNA994159 | ENA
Project description:Iron and heme play central roles in the production of red blood cells, but the underlying mechanisms remain incompletely understood. Heme-regulated eIF2α kinase (HRI) controls translation by phosphorylating eIF2α. Here, we investigate the global impact of iron, heme, and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. We validate the known role of HRI-mediated translational stimulation of integratedstressresponse mRNAs during iron deficiency in vivo. Moreover, we find that the translation of mRNAs encoding cytosolic and mitochondrial ribosomal proteins is substantially repressed by HRI during iron deficiency, causing a decrease in cytosolic and mitochondrial protein synthesis. The absence of HRI during iron deficiency elicits a prominent cytoplasmic unfolded protein response and impairs mitochondrial respiration. Importantly, ATF4 target genes are activated during iron deficiency to maintain mitochondrial function and to enable erythroid differentiation. We further identify GRB10 as a previously unappreciated regulator of terminal erythropoiesis.
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