The effect of PHZ-induced hemolytic anemia on HSCs [bisulfite-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE182058 | GEO | 2023/12/04
REPOSITORIES: GEO
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Project description:Hematopoietic stem cells (HSCs) are capable of regenerating the blood system, but the instructive cues that direct HSCs to regenerate particular lineages lost to the injury remain elusive. Here, we show that iron is increasingly taken up by HSCs during anemia and induces erythroid gene expression and regeneration in a Tet2-dependent manner. Lineage tracing of HSCs revealed that HSCs respond to hemolytic anemia by increasing erythroid output. The number of HSCs in the spleen, but not bone marrow, increased upon anemia and these HSCs exhibited enhanced proliferation, erythroid differentiation, iron uptake, and TET2 protein expression. Increased iron in HSCs promoted DNA demethylation and expression of erythroid genes. Suppressing iron uptake or TET2 expression impaired erythroid genes expression and erythroid differentiation of HSCs; iron supplementation, however, augmented these processes. These results establish that the physiological level of iron taken up by HSCs has an instructive role in promoting erythroid-biased differentiation of HSCs.
2023-12-04 | GSE178215 | GEO
Project description:Hematopoietic stem cells (HSCs) react to various stress conditions. However, it is unclear whether and how HSCs respond to severe anemia. Here, we demonstrate that upon induction of acute anemia, HSCs rapidly proliferate and enhance their erythroid differentiation potential. In severe anemia, lipoprotein profiles largely change and the concentration of ApoE increases. In HSCs, transcription levels of lipid metabolism-related genes, such as very low-density lipoprotein receptor (Vldlr), are upregulated. Stimulation of HSCs with ApoE enhances their erythroid potential, whereas HSCs in Apoe knockout mice do not respond to anemia induction. VldlrhighHSCs show higher erythroid potential, which is enhanced after acute anemia induction. VldlrhighHSCs are epigenetically distinct because of their low chromatin accessibility, and more chromatin regions are closed upon acute anemia induction. Chromatin regions closed upon acute anemia induction are mainly binding sites of Erg. Inhibition of Erg enhanced the erythroid differentiation potential of HSCs. Our findings indicate that lipoprotein metabolism plays a crucial role in HSC regulation under severe anemic conditions.
2024-08-07 | GSE274144 | GEO
Project description:Adult hematopoietic stem cells (HSCs) react to various stress conditions by rapidly proliferating and preferentially differentiating towards desired cell types. However, it is unclear whether and how HSCs respond to severe anemic conditions. Here we demonstrate that HSCs rapidly proliferate and enhance their erythroid potential upon induction of acute anemia. Under severe anemic conditions, the concentration of erythropoietin (EPO) does not increase in the bone marrow. Instead, lipoprotein profiles largely changed, and the concentration of apolipoprotein E (ApoE) increased. In HSCs, transcription levels of lipid metabolism-related genes such as very low-density lipoprotein receptor (Vldlr) were significantly up-regulated. Stimulation of HSCs with recombinant ApoE enhanced the erythroid potential, while HSCs of ApoE knockout mice did not respond to the hemolysis induction. We also found that VLDLRhighHSCs have higher erythroid differentiation potential, particularly after acute anemia induction. VLDLRhighHSCs were epigenetically distinct from VLDLRlowHSCs, as their chromatin accessibility was lower and more chromatin regions were closed upon acute anemia induction. Finally, we identified that the chromatin regions closed upon the acute anemia induction were mainly binding sites of a transcription factor Erg. Treatment of HSC with Erg inhibitor enhanced erythroid differentiation potential, as seen in the ApoE treatment. Our findings indicate that lipoprotein metabolism, particularly ApoE, plays a crucial role in HSC regulation under severe anemia conditions in a non-canonical fashion, unlike a conventional factor such as EPO.
2023-06-30 | GSE212392 | GEO
Project description:Mouse models have proven invaluable for understanding erythropoiesis. Here, we describe an autosomal recessive inherited anemia in the mouse mutant hem6. Hematologic and transplantation analyses revealed a mild, congenital, hypochromic, microcytic anemia intrinsic to the hematopoietic system that is associated with a decreased red blood cell zinc protoporphyrin to heme ratio, indicative of porphyrin insufficiency. Iron uptake experiments showed that hem6 reticulocytes are defective in heme production, but not cellular iron uptake defects. Male hem6 mice are infertile due to defects in sperm structure and motility. Through positional cloning and BAC complementation, we identified the gene responsible for the hem6 anemia. We hypothesized that the relative deficiency in erythroid-specific mRNAs in hem6 reticulocytes might be due to decreased mRNA stability. Indeed, serial microarray analysis of reticulocytes aged in vitro showed that numerous, abundantly expressed erythroid-specific transcripts decayed at faster rates in hem6 reticulocytes compared to control reticulocytes. Furthermore, these mRNAs also have progressively shorter poly (A) tails, suggesting a mechanism for the increased rate of decay. Keywords: serial time points Reticulocyte rich blood were collected and cultured ex vivo for 24 hours, samples were collected at 0, 12,24 hours for microarray analysis. There are 3 wild type (wt) biological replicates and 5 mutant (mut) biological replicates in each time point.
2009-10-12 | E-GEOD-16174 | biostudies-arrayexpress
Project description:Mouse models have proven invaluable for understanding erythropoiesis. Here, we describe an autosomal recessive inherited anemia in the mouse mutant hem6. Hematologic and transplantation analyses revealed a mild, congenital, hypochromic, microcytic anemia intrinsic to the hematopoietic system that is associated with a decreased red blood cell zinc protoporphyrin to heme ratio, indicative of porphyrin insufficiency. Iron uptake experiments showed that hem6 reticulocytes are defective in heme production, but not cellular iron uptake defects. Male hem6 mice are infertile due to defects in sperm structure and motility. Through positional cloning and BAC complementation, we identified the gene responsible for the hem6 anemia. We hypothesized that the relative deficiency in erythroid-specific mRNAs in hem6 reticulocytes might be due to decreased mRNA stability. Indeed, serial microarray analysis of reticulocytes aged in vitro showed that numerous, abundantly expressed erythroid-specific transcripts decayed at faster rates in hem6 reticulocytes compared to control reticulocytes. Furthermore, these mRNAs also have progressively shorter poly (A) tails, suggesting a mechanism for the increased rate of decay. Keywords: serial time points
2009-10-12 | GSE16174 | GEO
Project description:Iron is essential for all cells but is toxic in excess, so iron absorption and distribution are tightly regulated. Serum iron is bound to transferrin and primarily enters erythroid cells via receptor-mediated endocytosis of the transferrin receptor (Tfr1). Tfr1 is essential for developing erythrocytes and reduced Tfr1 expression is associated with anemia. The transcription factors STAT5A/B are activated by many cytokines, including erythropoietin. Stat5a/b-/- mice are severely anemic and die perinatally, but no link has been made to iron homeostasis. To study the function of STAT5A/B in vivo, we deleted the floxed Stat5a/b locus in hematopoietic cells with a Tie2-Cre transgene. These mice exhibited microcytic, hypochromic anemia, as did lethally irradiated mice transplanted with Stat5a/b-/- fetal liver cells. Flow cytometry and RNA analyses of erythroid cells from mutant mice revealed a 50% reduction in Tfr1 mRNA and protein. We detected STAT5A/B binding sites in the first intron of the Tfr1 gene and found that expression of constitutively active STAT5A in an erythroid cell line increased Tfr1 levels. Chromatin immunoprecipitation experiments confirmed the binding of STAT5A/B to these sites. We conclude that STAT5A/B is an important regulator of erythroid progenitor iron uptake via its control of Tfr1 transcription. Keywords: genetic modification
2008-06-13 | GSE11777 | GEO
Project description:We investigated the RBCs of a hemolytic anemia patient using quantitative proteomics. We used stable isotope dimethyl labeling to accurately quantify the RBC proteins. As controls, 1) samples of four healthy subjects were taken to account for normal variation in healthy individuals, and 2) samples of two non-spherocytic hemolytic anemia patients were taken to account for differences in protein levels due to elevated reticulocyte content. We used a combination of strong cation exchange (SCX) chromatography with nanoLC-MS/MS, enabling quantification of RBC proteins.
2016-09-27 | PXD001837 | Pride
Project description:Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. Recently a patient with MTO1 gene mutation presented with severe anemia was reported, which led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal due to niche-independent defective terminal erythroid differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver and this was followed by cytoplasmic iron accumulation. Overloaded cytoplasmic iron promoted heme biosynthesis, which induced an unfolded protein response via the IRE1-Xbp1 signaling pathway in Mto1 cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This novel non-energy-related mitochondrial iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in hematopoiesis.
2025-01-20 | PXD054386 | Pride
Project description:Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence resulting in severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.
2017-09-13 | PXD006054 | Pride
Project description:Schneider RK, Schenone M, Kramann R, Ferreira MV, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Gehrming U, Platzbecker U, Buesche G, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Nat Med, 2016.
Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100A8/S100A9 proteins in purified erythroblasts. S100A8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100A8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS.
2016-01-26 | MSV000079482 | MassIVE