Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis

Rossmann, Marlies P.; Hoi, Karen; Chan, Victoria; Abraham, Brian J.; Yang, Song; Mullahoo, James; Papanastasiou, Malvina; Wang, Ying; Elia, Ilaria; Perlin, Julie R.; Hagedorn, Elliott J.; Hetzel, Sara; Weigert, Raha; Vyas, Sejal; Nag, Partha P.; Sullivan, Lucas B.; Warren, Curtis R.; Dorjsuren, Bilguujin; Greig, Eugenia Custo; Adatto, Isaac; Cowan, Chad A.; Schreiber, Stuart L.; Young, Richard A.; Meissner, Alexander; Haigis, Marcia C.; Hekimi, Siegfried; Carr, Steven A.; Zon, Leonard I.

doi:10.1126/science.aaz2740

Cited by 40 publications

(34 citation statements)

References 70 publications

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“…Changes in mitochondrial metabolism, oxidative stress, or regulation of mitochondria abundance within cells can be accompanied by changes in mitochondrial morphology. Mitochondrial functions are tightly regulated over erythroid differentiation ( Oburoglu et al, 2014 , 2016 ; Gonzalez-Menendez et al, 2021 ; Rossmann et al, 2021 ). Mitochondria fragmentation is an essential step for maturation ( Gonzalez-Ibanez et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

et al. 2022

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Throughout mammal erythroid differentiation, erythroblasts undergo enucleation and organelle clearance becoming mature red blood cell. Organelles are cleared by autophagic pathways non-specifically targeting organelles and cytosolic content or by specific mitophagy targeting mitochondria. Mitochondrial functions are essential to coordinate metabolism reprogramming, cell death, and differentiation balance, and also synthesis of heme, the prosthetic group needed in hemoglobin assembly. In mammals, mitochondria subcellular localization and mitochondria interaction with other structures as endoplasmic reticulum and nucleus might be of importance for the removal of the nucleus, that is, the enucleation. Here, we aim to characterize by electron microscopy the changes in ultrastructure of cells over successive stages of human erythroblast differentiation. We focus on mitochondria to gain insights into intracellular localization, ultrastructure, and contact with other organelles. We found that mitochondria are progressively cleared with a significant switch between PolyE and OrthoE stages, acquiring a rounded shape and losing contact sites with both ER (MAM) and nucleus (NAM). We studied intracellular vesicle trafficking and found that endosomes and MVBs, known to be involved in iron traffic and heme synthesis, are increased during BasoE to PolyE transition; autophagic structures such as autophagosomes increase from ProE to OrthoE stages. Finally, consistent with metabolic switch, glycogen accumulation was observed in OrthoE stage.

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Section: Resultsmentioning

confidence: 99%

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

et al. 2022

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“…The development of HSPCs into erythroid cells can serve as a cell model for exploring the pathogenesis of hematological disorders associated with mitochondrial dysregulation [19]. We developed an ex vivo culture system to differentiate human HSPCs into erythroid cells, in which the OXPHOS pathway is inhibited by Rot [31], a specific inhibitor of the OXPHOS pathway. A greater reduction in the mitochondrial membrane potential (P3) indicates greater suppression of the OXPHOS pathway [32].…”

Section: Resultsmentioning

confidence: 99%

Oxidative phosphorylation pathway disruption is an alternative pathological mechanism leading to Diamond-Blackfan anemia

Xiao

Zhang

Xin

et al. 2022

Preprint

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Diamond-Blackfan anemia (DBA) is a rare congenital disorder characterized by the failure of erythroid progenitor differentiation; however, the molecular mechanisms leading to erythroid defects remain unclear. By analyzing the transcriptomic profiles of bone marrow from patients with DBA (n = 10), we identified the oxidative phosphorylation (OXPHOS) pathway as a possible cause of DBA. We established a DBA cell model using differentiating hematopoietic stem progenitor cells in which the OXPHOS pathway had been suppressed to completely recapitulate the defects of erythroid progenitor differentiation, ribosome biogenesis, and heme biosynthesis, which are representative characteristics of patients with DBA. Disruption of the OXPHOS pathway led to ribosomal defects and associated erythroid defects via the abolishment of RanGAP1, which is pivotal in the RNA transport pathway. The established DBA cells exhibited an overall reduction in ribosomal proteins, but not the composition of ribosomal proteins in the ribosome, which altered the translation of a subset of transcripts specific for erythropoiesis. We revealed that the OXPHOS pathway participates in erythropoiesis, particularly at an early stage, and the relationship between the OXPHOS pathway and erythropoiesis was reinforced. CoQ10, an activator of OXPHOS, largely rescued the erythroid defects in DBA cells. Our results reveal that OXPHOS repression is an alternative pathological mechanism leading to DBA, demonstrating its potential as a therapeutic pathway in DBA.

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“…Deletion of mitochondria factors resulted in metabolic changes and histone hyperacetylation, further leading to the impaired erythrocyte differentiation. Moreover, the transcription elongation factor TIF1γ directly regulates mitochondrial genes and histone methylation during erythrocyte differentiation ( Rossmann et al, 2021 ). These studies suggest that the mitochondria biogenesis and function are highly regulated during normal erythropoiesis through transcriptional, epigenetic and post-transcriptional mechanisms, which may explain the specific defects observed in smarca5 -deficient erythroid cells.…”

Section: Discussionmentioning

confidence: 99%

The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling

Ding

Zhao

et al. 2021

eLife

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Although thrombosis has been extensively studied using various animal models, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that smarca5-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus. We further used the anti-thrombosis drugs to treat smarca5zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5zko1049a and their siblings and found that both the chromatin accessibility at the keap1a promoter and expression of keap1a were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of hmox1a, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon smarca5 deletion. Importantly, overexpression of keap1a or knockdown of hmox1a partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the RBC aggregation in smarca5 mutants. Together, our study using zebrafish smarca5 mutants characterizes a novel role for smarca5 in RBC aggregation, which may provide a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.

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Cell-specific transcriptional control of mitochondrial metabolism by TIF1γ drives erythropoiesis

Cited by 40 publications

References 70 publications

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

Oxidative phosphorylation pathway disruption is an alternative pathological mechanism leading to Diamond-Blackfan anemia

The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling

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