Lipidomics of GATA1 mutant cells during erythroid maturation
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive HF
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Josh J. Coon
PROVIDER: MSV000092894 | MassIVE |
REPOSITORIES: MassIVE
Similar Datasets
Project description:RP-LC-MS lipidomics data was collected to understand the role of GATA1 during erythroid maturation. GATA1 mutants and WT cells were treated with or without beta-estradiol. GATA1 mutant cells were additionally treated with or without 5-ALA.
| MSV000092894 | GNPS
Project description:Alas2 gene encodes the rate-limiting enzyme in heme biosynthesis. CRISPR/Cas9-mediated ablation of two Alas2 intronic cis-elements strongly reduced GATA-1-induced Alas2 transcription, heme biosynthesis, and GATA-1 regulation of other vital constituents of the erythroid cell transcriptome. Bypassing Alas2 function in Alas2 cis-element-mutant (double mutant) cells by providing its catalytic product 5-aminolevulinic acid (5-ALA) rescued heme biosynthesis and the GATA-1-dependent genetic network. We discovered a GATA factor- and heme-dependent circuit that establishes the erythroid cell transcriptome. G1E-ER-GATA-1 WT and double mutant cells were examined. Untreated WT, beta-estradiol-treated WT, beta-estradiol-treated double-mutant, and beta-estradiol/5-ALA-treated double-mutant cells were subjected to RNA-seq.
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Project description:Proteasome inhibition constitutes a cornerstone of multiple myeloma (MM) treatment, with bortezomib, carfilzomib and ixazomib approved for clinical use. We observed a consistent and highly significant increase in the reticulocyte count during treatment with carfilzomib-based regimens in patients with relapsed MM, an observation not made in a matched cohort of bortezomib-treated patients. As this increased reticulocytosis was neither associated with elevated hemoglobin levels nor with hemolysis, we subsequently performed in vitro experiments to unravel the underlying mechanisms of this clinical observation. While carfilzomib did not affect erythroid differentiation of CD34+ hematopoietic progenitor cells, both continuous and pulse exposure to carfilzomib significantly impaired terminal maturation of purified primary reticulocytes towards erythrocytes. These results indicate that carfilzomib significantly impairs terminal erythroid maturation, independent of erythroid commitment, expansion or differentiation. Our results report the first pharmacologically induced delay in erythroid maturation as a mechanism for carfilzomib-induced reticulocytosis in MM patients. Quantitative proteomics using LC-MS/MS were performed to assess whether carfilzomib treatment alters the protein composition of reticulocytes
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Project description: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 G1-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. Myc prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. When over-expressed 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. These studies reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells. Our findings further support the emerging notion that Myc regulates chromatin structure by regulating global histone acetylation states. Five groups with three biological replicates in each.
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Project description:We employed a gene complementation strategy combined with microarray screening to identify miRNAs involved in the formation of erythroid (red blood) cells. To search for GATA-1-regulated erythroid miRNAs, we used the Gata-1– erythroblast line G1E. These cells proliferate in culture as immature erythroid precursors and undergo terminal maturation when GATA-1 activity is restored. G1E-ER4 is a sub-line stably expressing an estrogen-activated form of GATA-1 (GATA-1 fused to the ligand binding domain of the estrogen receptor). Treatment of G1E-ER4 cells with estradiol induces a GATA-1-regulated program of gene expression with concomitant cellular maturation. We used a microarray to evaluate the expression of 292 different miRNAs in G1E-ER4 cells at 0 versus 24 hours after GATA-1 activation. Affymetrix gene expression profiling has previously been deposited (GEO accession no. GSE628). Keywords: microRNA analysis of a cell-line model of erythroid maturation Two condition experiment, 3 replicates each (independently grown and harvested) of untreated and estradiol-treated (24hrs) G1E-ER4 cells, which express an estrogen-responsive form of the GATA-1 transcription factor. Each sample is compared to a common reference sample, comprised of an equal mixture of all 6 experimental samples.
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Project description: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 G1-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. Myc prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. When over-expressed 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. These studies reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells. Our findings further support the emerging notion that Myc regulates chromatin structure by regulating global histone acetylation states.
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