FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA453546 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Erythropoietin (EPO) signaling is critical to many processes essential to terminal erythropoiesis. Despite the centrality of iron metabolism to erythropoiesis, the mechanisms by which EPO regulates iron status are not well-understood. To this end, here we profiled gene expression in EPO-treated 32D pro-B cells and developing fetal liver erythroid cells to identify additional iron regulatory genes. We determined that FAM210B, a mitochondrial inner-membrane protein, is essential for hemoglobinization, proliferation, and enucleation during terminal erythroid maturation. Fam210b deficiency led to defects in mitochondrial iron uptake, heme synthesis, and iron-sulfur cluster formation. These defects were corrected with a lipid-soluble, small-molecule iron transporter, hinokitiol, in Fam210b-deficient murine erythroid cells and zebrafish morphants. Genetic complementation experiments revealed that FAM210B is not a mitochondrial iron transporter but is required for adequate mitochondrial iron import to sustain heme synthesis and iron-sulfur cluster formation during erythroid differentiation. FAM210B was also required for maximal ferrochelatase activity in differentiating erythroid cells. We propose that FAM210B functions as an adaptor protein that facilitates the formation of an oligomeric mitochondrial iron transport complex, required for the increase in iron acquisition for heme synthesis during terminal erythropoiesis. Collectively, our results reveal a critical mechanism by which EPO signaling regulates terminal erythropoiesis and iron metabolism.
| S-EPMC6314115 | biostudies-literature
Project description:To understand the downstream pathways of the Epo signaling, we have emplyed microarray gene expression profiling to discover the gene expression changes in 32D cells upon the Epo stimulation.
2018-10-26 | GSE113657 | GEO
Project description:In mice lacking the heme exporter, FLVCR, differentiation fails at the CFU-E/proerythroblast stage from excessive heme and reactive oxygen species. We show that Flvcr1-deleted CFU-E/proerythroblasts have low GATA1 mRNA and GATA1-target gene mRNAs along with increased ribosomal protein mRNAs as a direct result of increased heme. Thus heme increases ribosomal protein transcription when globin production needs to be increased, and when heme is excessive, GATA1 is reduced allowing for normal termination of erythroid differentiation. This demonstrates that heme and GATA1 are co-master regulators of erythroid differentiation.
2019-02-07 | GSE94905 | GEO
Project description:In mice lacking the heme exporter, FLVCR, differentiation fails at the CFU-E/proerythroblast stage from excessive heme and reactive oxygen species. We show that Flvcr1-deleted CFU-E/proerythroblasts have low GATA1 mRNA and GATA1-target gene mRNAs along with increased ribosomal protein mRNAs as a direct result of increased heme. Thus heme increases ribosomal protein transcription when globin production needs to be increased, and when heme is excessive, GATA1 is reduced allowing for normal termination of erythroid differentiation. This demonstrates that heme and GATA1 are co-master regulators of erythroid differentiation.
2019-02-07 | GSE94898 | GEO
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.
2016-01-07 | GSE74371 | GEO
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.
2016-01-07 | E-GEOD-74371 | biostudies-arrayexpress
Project description:Heme and GATA1 coordinately regulate erythroid differentiation
| PRJNA374843 | ENA
Project description:CRISPR/Cas9-mediated ablation of two Alas2 intronic cis-elements in G1E-ER-GATA1 cells 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 a subset of GATA-1-dependent genetic network. Using the same system, we discovered a GATA-1- and heme-dependent circuit that regulates chromatin accessibility during erythroid maturation.
2018-05-30 | GSE114996 | GEO
Project description:After a bloodmeal, mosquitoes import heme into the midgut epithelium. Heme acts as an essential signal for oogenesis in Aedes aegypti. However, the mechanisms behind heme import in Aedes aegypti are largely unexplored. In this study, RNA sequencing data from 4 different Aedes aegypti cell culture experiments where exposure to an overabundance or deficiency of heme was examined to identify heme-responsive genes. Zinc mesoporphyrin (ZnMP), a heme fluorescent analog, was used to measure changes in heme uptake prior to mRNA sequencing. A soft cluster analysis was performed to identify genes encoding potential membrane bound importers and exporters based on expression profiles across the samples for each experiment. Stronger candidates were obtained by comparing genes in each dataset to each other. When comparing all datasets to each other, 223 candidate genes with expression pattern changes consistent with importers were found to be heme-regulated in only 2 datasets, 46 were heme-regulated in 3 datasets and 2 was heme-regulated in all 4 datasets. In contrast, 114 candidate genes with patterns consistent with exporters were common to only 2 datasets, with just 11 present in 3 of the 4 datasets. A large number of genes containing transmembrane domains were isolated across the 4 datasets which showed downregulation or upregulation in response to heme overexposure conditions indicating the possibility that heme membrane bound import and export genes were identified respectively, with the reverse trend observed in the presence of heme deficiency. However, few transporter candidate genes were identified that showed high differential expression (above 4-fold or below 1/4th fold). Ultimately, as few strong candidates were identified by these studies, we consider the possibility that each cell line could have a redundant system of heme import, whereby multiple transport proteins each contribute to the total heme accumulation in the cell. Alternatively, it is possible that these cells lines do not regulate heme transport at the transcript level, but rather do so post-translationally.
2020-08-03 | GSE140752 | GEO
Project description:We have tested the effect of iron on the gene expression profile in human leukemia cells with properties of erythroid differentiation.
2014-09-08 | GSE52087 | GEO