EDAG mediates Hsp70 nuclear localization in erythroblasts and rescues dyserythropoiesis in myelodysplastic syndrome

Dong, Xian-Zi; Zhao, Ke; Zheng, Weiwei; Xu, Chi; Zhang, Mei-Jiang; Yin, Rong‐Hua; Gao, Rui; Tang, Liujun; Liu, Jin‐Fang; Chen, Hui; Yao, Zhan; Yu, Miao; Ge, Chang‐Hui; Gao, Huiying; Li, Xiu; Luo, Teng; Ning, Hongmei; Yang, Xiaoming; Li, Chang‐Yan

doi:10.1096/fj.201902946r

Cited by 10 publications

(4 citation statements)

References 34 publications

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“…This hypothesis is supported by our western blot as well as RNA-seq analysis (Supplemental Figure 13A-C). It has also been reported that abnormal expression or function of HSP70 can promote ineffective erythropoiesis in β-thalassemia 43,44 , MDS 23,45 , and Diamond-Blackfan anemia (DBA) 24,46 . In addition, an increasing number of studies have revealed other functions of HSP70 chaperone proteins and linked the methylation of non-histone proteins to the regulation of gene transcription 33,47 .…”

Section: Discussionmentioning

confidence: 99%

Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation

Li¹,

Liu²,

Xue³

et al. 2023

haematol

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Enhancer of zeste homolog 2 (EZH2) is the lysine methyltransferase of polycomb repressive complex 2 (PRC2) that catalyzes H3K27 tri-methylation. Aberrant expression and loss-of-function mutations of EZH2 have been demonstrated to be tightly associated with the pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as myelodysplastic syndrome (MDS). However, the function and mechanism of EZH2 in human erythropoiesis still remains largely unknown. Here, we demonstrated that EZH2 regulates human erythropoiesis in a stage-specific, dual-function manner by catalyzing histone and non-histone methylation. During the early erythropoiesis, EZH2 deficiency caused cell cycle arrest in the G1 phase, which impaired cell growth and differentiation. ChIP-seq and RNA-seq discovered that EZH2 knockdown caused a reduction of H3K27me3 and upregulation of cell cycle protein-dependent kinase inhibitors. In contrast, EZH2 deficiency led to the generation of abnormal nuclear cells and impaired enucleation during the terminal erythropoiesis. Interestingly, EZH2 deficiency downregulated the methylation of HSP70 by directly interacting with HSP70. RNA-seq analysis revealed that the expression of AURKB was significantly downregulated in response to EZH2 deficiency. Furthermore, treatment with an AURKB inhibitor and shRNA-mediated AURKB knockdown also led to nuclear malformation and decreased enucleation efficiency. These findings strongly suggest that EZH2 regulates terminal erythropoiesis through a HSP70 methylation-AURKB axis. Our findings have implications for improved understanding of ineffective erythropoiesis with EZH2 dysfunction.

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Section: Discussionmentioning

confidence: 99%

Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation

Li¹,

Liu²,

Xue³

et al. 2023

haematol

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“…These results suggest that Hemgn deletion accelerates HSPCs response to IFN‐ γ via suppressing TC45 activity. Given that Hemgn deficiency does not alter TC45 expression and HEMGN can interact with a variety of nuclear proteins, [ 14 , 15 , 48 ] the investigation of interactions between HEMGN and Stat1/TC45 may help to explain the exact mechanism by which HEMGN regulates TC45‐medicated Stat1 dephosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Hemgn Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN‐γ Signaling

et al. 2021

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Hematopoietic stem and progenitor cells (HSPCs) possess the remarkable ability to regenerate the whole blood system in response to ablated stress demands. Delineating the mechanisms that maintain HSPCs during regenerative stresses is increasingly important. Here, it is shown that Hemgn is significantly induced by hematopoietic stresses including irradiation and bone marrow transplantation (BMT). Hemgn deficiency does not disturb steady-state hematopoiesis in young mice. Hemgn −/-HSPCs display defective engraftment activity during BMT with reduced homing and survival and increased apoptosis. Transcriptome profiling analysis reveals that upregulated genes in transplanted Hemgn −/− HSPCs are enriched for gene sets related to interferon gamma (IFN-𝜸) signaling. Hemgn −/− HSPCs show enhanced responses to IFN-𝜸 treatment and increased aging over time. Blocking IFN-𝜸 signaling in irradiated recipients either pharmacologically or genetically rescues Hemgn −/-HSPCs engraftment defect. Mechanistical studies reveal that Hemgn deficiency sustain nuclear Stat1 tyrosine phosphorylation via suppressing T-cell protein tyrosine phosphatase TC45 activity. Spermidine, a selective activator of TC45, rescues exacerbated phenotype of HSPCs in IFN-𝜸-treated Hemgn −/− mice. Collectively, these results identify that Hemgn is a critical regulator for successful engraftment and reconstitution of HSPCs in mice through negatively regulating IFN-𝜸 signaling. Targeted Hemgn may be used to improve conditioning regimens and engraftment during HSPCs transplantation.

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“…The transient activation of cysteine aspartate specific protease-3 (Caspase-3) is necessary for erythroblasts maturation, and GATA-1 is also essential for the maturation of erythroblasts ( Dong et al, 2020 ). In the terminal stage of normal erythroid cells differentiation and maturation, Heat shock protein 70 (HSP70) is translocated from the cytoplasm into the nucleus, and it can serve as a chaperone protein within the nucleus to shield the GATA-1 from being cleaved by Caspase-3 ( Ribeil et al, 2007 ; Arlet et al, 2014 ).…”

Section: Ie In β-Thalmentioning

confidence: 99%

The interactions between ineffective erythropoiesis and ferroptosis in β-thalassemia

Lin,

Zheng,

Chen

et al. 2024

Front. Physiol.

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In Guangxi, Hainan, and Fujian Province in southern China, β-thalassemia is a frequent monogenic hereditary disorder that is primarily defined by hemolytic anemia brought on by inefficient erythropoiesis. It has been found that ineffective erythropoiesis in β-thalassemia is closely associated with a high accumulation of Reactive oxygen species, a product of oxidative stress, in erythroid cells. During recent years, ferroptosis is an iron-dependent lipid peroxidation that involves abnormalities in lipid and iron metabolism as well as reactive oxygen species homeostasis. It is a recently identified kind of programmed cell death. β-thalassemia patients experience increased iron release from reticuloendothelial cells and intestinal absorption of iron, ultimately resulting in iron overload. Additionally, the secretion of Hepcidin is inhibited in these patients. What counts is both ineffective erythropoiesis and ferroptosis in β-thalassemia are intricately linked to the iron metabolism and Reactive oxygen species homeostasis. Consequently, to shed further light on the pathophysiology of β-thalassemia and propose fresh ideas for its therapy, this paper reviews ferroptosis, ineffective erythropoiesis, and the way they interact.

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EDAG mediates Hsp70 nuclear localization in erythroblasts and rescues dyserythropoiesis in myelodysplastic syndrome

Cited by 10 publications

References 34 publications

Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation

Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation

Hemgn Protects Hematopoietic Stem and Progenitor Cells Against Transplantation Stress Through Negatively Regulating IFN‐γ Signaling

The interactions between ineffective erythropoiesis and ferroptosis in β-thalassemia

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