Histone deacetylase 2 is required for chromatin condensation and subsequent enucleation of cultured mouse fetal erythroblasts

Ji, Peng; Yeh, Victor; Ramı́rez, Tzutzuy; Murata‐Hori, Maki; Lodish, Harvey F.

doi:10.3324/haematol.2010.029827

Cited by 88 publications

(88 citation statements)

References 32 publications

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“…Our data demonstrates that normal down-regulation of Myc in late stage erythroid cells is essential for nuclear condensation and enucleation, revealing a novel role for Myc in mammalian erythropoiesis. Myc is down-regulated during the late stages of erythroid maturation, concomitant with the global histone deacetylation that is critical for erythroid nuclear condensation and enucleation (43,44). Ectopic Myc expression at physiological levels that did not induce cell cycle re-entry was sufficient to block the global histone deacetylation and inhibit nuclear condensation and enucleation.…”

Section: Discussionmentioning

confidence: 98%

“…Pharmacological inhibition of histone deacetylases (HDACs) has been reported to block chromatin condensation and enucleation in erythroid cells, demonstrating that global histone deacetylation observed during late stage erythroid maturation is necessary for erythroid nuclear condensation and enucleation (43,44). Recent studies have shown that Myc regulates global chromatin structure by influencing widespread histone modifications (45)(46)(47).…”

Section: Ectopic Myc Expression Inhibits Nuclear Condensation and Hismentioning

confidence: 99%

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Down-regulation of Myc Is Essential for Terminal Erythroid Maturation

Jayapal

Lee

et al. 2010

Journal of Biological Chemistry

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Terminal differentiation of mammalian erythroid progenitors involves 4 -5 cell divisions and induction of many erythroid important genes followed by chromatin and nuclear condensation and enucleation. The protein levels of c-Myc (Myc) are reduced dramatically during late stage erythroid maturation, coinciding with cell cycle arrest in G 1 phase and enucleation, suggesting possible roles for c-Myc in either or both of these processes. Here we demonstrate that ectopic Myc expression affects terminal erythroid maturation in a dose-dependent manner. Expression of Myc at physiological levels did not affect erythroid differentiation or cell cycle shutdown but specifically blocked erythroid nuclear condensation and enucleation. Continued Myc expression prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. The histone acetyltransferase Gcn5 was up-regulated by Myc, and ectopic Gcn5 expression partially blocked enucleation and inhibited the late stage erythroid nuclear condensation and histone deacetylation. When overexpressed at levels higher than the physiological range, Myc blocked erythroid differentiation, and the cells continued to proliferate in cytokine-free, serum-containing culture medium with an early erythroblast morphology. Gene expression analysis demonstrated the dysregulation of erythropoietin signaling pathway and the up-regulation of several positive regulators of G 1 -S cell cycle checkpoint by supraphysiological levels of Myc. These results reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells.Mammalian terminal erythroid development is a precisely regulated process involving rapid proliferation and serial morphological changes of committed erythroid progenitors (colony forming units-erythroid, or CFU-E) 5 to form mature erythrocytes. The initial stages of terminal erythroid maturation are highly dependent on erythropoietin (1), whose roles in activation of erythroid specific genes, terminal proliferation, and protection against apoptosis are well understood (2). This is followed by an erythropoietin-independent, fibronectin-dependent phase where survival and proliferation of the erythroblasts require signaling by ␣4␤1 integrins (3). Upon erythropoietin stimulation, CFU-E progenitors undergo 4 -5 cell divisions accompanied by a decrease in cell size, increase in hemoglobin content, and nuclear condensation followed by withdrawal from the cell cycle (4). Late stage mammalian erythroblasts undergo nuclear condensation and enucleate by extrusion of the pycnotic nucleus surrounded by a thin layer of cytoplasm and cell membrane (5-7). The molecular mechanisms that regulate this hallmark process remain to be fully elucidated. We previously reported that Rac GTPases and their downstream effector mDia2 play important roles in the cytoskeletal reorganization leading to the extrusion of the pycnotic nucleus from late stage erythroblasts (8). Nevertheless, the mechanisms regu...

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Section: Discussionmentioning

confidence: 98%

Section: Ectopic Myc Expression Inhibits Nuclear Condensation and Hismentioning

confidence: 99%

Down-regulation of Myc Is Essential for Terminal Erythroid Maturation

Jayapal

Lee

et al. 2010

Journal of Biological Chemistry

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“…The study by Ji et al 10 published in this issue of the Journal provides the first detailed analyses of the expression of different HDAC isoforms during maturation of murine erythrocytes. Previous investigators had already identified that HDAC are required for chromatin condensation prior to enucleation of murine erythroblasts immortalized with the Friend virus.…”

Section: A Newly Identified Role For Histone Deacetylases In Erythropmentioning

confidence: 99%

“…APHA 9 and UBHA 24 were identified by screening a library of 24 new HDACi for their ability to reactivate g-globin expression in erythroblasts generated ex-vivo from normal donors and from β°-thalassemic patients. 16 The paper by Ji et al 10 led us to perform re-analyses for signs of enucleation in May-GrunwaldGiemsa stained smears prepared from cells obtained in the course of this previous study. Pyrenocytes (arrows) and ghosts of reticulocytes (arrow-head, reticulocytes do not survive the shear force of the centrifugation process) were easily detectable on smears of human erythroblasts induced to mature with erythropoietin for 4 days (control).…”

Section: Recent Advances In Translational Research On Histone Deacetymentioning

confidence: 99%

“…19 More recent genetic and mass spectrometry studies have identified that the specificity of the silencing may be provided by recruitment to the complex of BCL11A which docks the HDAC to the g-globin regulatory region. 20 (iii) Chromatin condensation: in this issue of the journal Ji et al 10 describe that chromatin condensation in preparation for orthochromatic erythroblast formation is regulated by HDAC2. It is possible that, by deacetylating the centromere-specific histone H3.3, 7 HDAC2 is also responsible for dissociation of the centromeres from the fibers of the spindle.…”

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Erythroblast enucleation

Migliaccio¹

2010

Haematologica

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E rythrocytes, commonly called red cells, are the cellular elements of blood that perform the unique function of ensuring proper oxygen delivery to the tissues. 1 The average blood volume for an adult is 5 liters (55-75 mL/Kg of body weight) and the blood contains approximately 10 9 red cells per milliliter. Red cells do not normally contain a nucleus and are unable to proliferate. They have a limited life-span (~120 days in humans) and are replenished by the constant generation of new cells from hematopoietic stem/progenitor cell compartments. The process of erythropoiesis includes two phases: a first commitment/proliferation phase in which stem/progenitor cells are induced by extrinsic (growth factors) and intrinsic (transcription factors) factors to expand and to activate the differentiation programs and a second maturation phase in which the first morphologically recognizable erythroid cell (the pro-erythroblast) becomes unable to proliferate and undergoes cytoplasmic and nuclear alterations. Cytoplasmic maturation includes loss of mitochondria, reduction of ribosome numbers and reorganization of the microfilament structure and is mediated by the autophagic program, a proteosome-dependent pathway of proteolysis developed by eukaryotic cells to survive starvation (but which may lead to death).2 Nuclear changes involve chromosome condensation and loss of cytoplasmic-nuclear junctions in preparation for enucleation and may represent an extreme case of asymmetric division (Figure 1). The enucleation processThe earliest recognizable erythroid cell, the pro-erythroblast, undergoes four or five mitotic divisions which generate, in sequence, basophilic, polychromatophilic and orthochromatic erythroblasts ( Figure 2A). The morphological differences between these cells reflect progressive accumulation of hemoglobin (and other erythroid-specific proteins) and decrease in nuclear size and activity.1 The nucleus becomes dense, because of chromosome condensation, is isolated from the cytoplasm by a ring of cytoplasmic membranes and moves to one side of the cell. 3 The orthochromatic erythroblast is then partitioned into two daughter structures, the reticulocyte, containing most of the cytoplasm, and the pyrenocyte, containing the condensed nucleus encased in a thin cytoplasmic layer. This partitioning is called nuclear extrusion or enucleation and is favored by interaction between the erythroblasts and the macrophage within the erythroid niche, an anatomical structure first identified by Bessis in 1958 4 (Figure 1). Since most of the pyrenocytes are engulfed and degraded by the macrophage, 3 their recognition as bona fide cells occurred when they were discovered in the blood of embryos (which contains limited numbers of macrophages) where they are released during the enucleation process of primitive mammalian erythroblasts. 5Enucleated erythrocytes are present in the blood of all mammals, suggesting that enucleation provides an evolutionary advantage. Studies in lower eukaryotes (budding yeast and Drosophila) are clarifyi...

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Transferrin receptor 1 is required for enucleation of mouse erythroblasts during terminal differentiation

et al. 2019

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Enucleation is the process whereby the nucleus is extruded from the erythroblast during late stage mammalian erythropoiesis. However, the specific signaling pathways involved in this process remain unclear. To better understand the mechanisms underlying erythroblast enucleation, we investigated erythroblast enucleation using both the spleens of adult mice with phenylhydrazine‐induced anemia and mouse fetal livers. Our results indicated that both iron‐bound transferrin (holo‐Tf) and the small‐molecule iron transporter hinokitiol with iron ions (hinokitiol plus iron) promote hemoglobin synthesis and the enucleation of mouse spleen‐derived erythroblasts. Although an antitransferrin receptor 1 (TfR1) monoclonal antibody inhibited both enucleation and hemoglobin synthesis promoted by holo‐Tf, it inhibited only enucleation, but not hemoglobin synthesis, promoted by hinokitiol plus iron. Furthermore, siRNA against mouse TfR1 were found to suppress the enucleation of mouse fetal liver‐derived erythroblasts, and the endocytosis inhibitor MitMAB inhibited enucleation, hemoglobin synthesis, and the internalization of TfR1 promoted by both types of stimuli. Collectively, our results suggest that TfR1, iron ions, and endocytosis play important roles in mouse erythroblast enucleation.

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Histone deacetylase 2 is required for chromatin condensation and subsequent enucleation of cultured mouse fetal erythroblasts

Cited by 88 publications

References 32 publications

Down-regulation of Myc Is Essential for Terminal Erythroid Maturation

Down-regulation of Myc Is Essential for Terminal Erythroid Maturation

Erythroblast enucleation

Transferrin receptor 1 is required for enucleation of mouse erythroblasts during terminal differentiation

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