Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Rb Intrinsically Promotes Erythropoiesis by Coupling Cell Cycle Exit with Mitochondrial Biogenesis

ABSTRACT: Regulation of the cell cycle is intimately linked to erythroid differentiation, yet how these processes are coupled is not well understood. To gain insight into this coordinate regulation, we examined the role that the retinoblastoma protein (Rb), a central regulator of the cell cycle, plays in erythropoiesis. We found that Rb serves a cell-intrinsic role and its absence causes ineffective erythropoiesis, with a differentiation block at the transition from early to late erythroblasts. Unexpectedly, in addition to a failure to properly exit the cell cycle, mitochondrial biogenesis fails to be upregulated concomitantly, contributing to this differentiation block. The link between erythropoiesis and mitochondrial function was validated by inhibition of mitochondrial biogenesis. Erythropoiesis in the absence of Rb resembles the human myelodysplastic syndromes, where defects in cell cycle regulation and mitochondrial function frequently occur. Our work demonstrates how these seemingly disparate pathways play a role in coordinately regulating cellular differentiation. Keywords: disease state analysis

ORGANISM(S): Mus musculus

PROVIDER: GSE9717 | GEO | 2008/02/14

SECONDARY ACCESSION(S): PRJNA103623

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling of mouse CD71+/Ter-119+ bone marrow erythroid progenitors from Rb-null animals and controls reveals Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis

Project description:Regulation of the cell cycle is intimately linked to erythroid differentiation, yet how these processes are coupled is not well understood. To gain insight into this coordinate regulation, we examined the role that the retinoblastoma protein (Rb), a central regulator of the cell cycle, plays in erythropoiesis. We found that Rb serves a cell-intrinsic role and its absence causes ineffective erythropoiesis, with a differentiation block at the transition from early to late erythroblasts. Unexpectedly, in addition to a failure to properly exit the cell cycle, mitochondrial biogenesis fails to be upregulated concomitantly, contributing to this differentiation block. The link between erythropoiesis and mitochondrial function was validated by inhibition of mitochondrial biogenesis. Erythropoiesis in the absence of Rb resembles the human myelodysplastic syndromes, where defects in cell cycle regulation and mitochondrial function frequently occur. Our work demonstrates how these seemingly disparate pathways play a role in coordinately regulating cellular differentiation. Experiment Overall Design: Microarray expression analysis from sorted CD71+/Ter-119+ bone marrow erythroid progenitors of Rb-null animals and controls. The Rb-null genotype was EpoR-GFPcre/+; Rb fl/fl and the control genotype was EpoR-GFPcre/+; Rb fl/+. We have analyzed 3 Rb-null datasets and 3 control datasets.

2008-04-07 | E-GEOD-9717 | biostudies-arrayexpress

Mus musculus

Project description:Rb Intrinsically Promotes Erythropoiesis by Coupling Cell Cycle Exit with Mitochondrial Biogenesis

| PRJNA103623 | ENA

A transcriptional regulatory network connects mitochondrial biogenesis and metabolic shift with stem cell commitment to hepatic differentiation

Project description:Mitochondrial biogenesis and metabolism recently emerged as critical modulators of stemness properties and differentiation programmes. The increase in mitochondrial biogenesis and metabolic shift toward increased oxidative phosphorylations (OXPHOS) appear as hallmarks of stem cell differentiation processes. While several mechanisms support the involvement of mitochondrial biogenesis and function in the regulation of stem cell differentiation, the mechanisms triggering mitochondrial biogenesis in the context of cell differentiation remain elusive. In this study, we performed transcriptomic and bioinformatic analyses in order to get deeper insights into the cross-regulation of mitochondrial biogenesis and hepatogenic differentiation of human bone marrow mesenchymal stem cells (BM-MSCs). We identified a transcriptional regulatory network involved in the co-regulation of stem cell differentiation and mitochondrial biogenesis.

2017-08-23 | GSE75184 | GEO

RNA-seq transcriptional profiling in human primary fetal and adult CD34+ hematopoietic stem/progenitor cells (HSPCs) erythroid progenitor cells (ProEs)

Project description:Advances in sequencing-based genomic profiling present a new challenge of explaining how changes in DNA/RNA are translated into proteins linking genotypes to phenotypes. The developing erythroid cells require highly coordinated gene expression and metabolism, and serve as a unique model in dissecting regulatory events in development and disease. Here we compare the proteomic and transcriptomic changes in human hematopoietic stem/progenitor cells and lineage-committed erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Two principal mitochondrial factors TFAM and PHB2 are tightly regulated at the protein level and indispensable for mitochondria and erythropoiesis. mTORC1 signaling is progressively enhanced to promote translation of mitochondrial proteins during erythroid specification. Genetic and pharmacological perturbation of mTORC1 or mitochondria impairs erythropoiesis. Our studies suggest a new mechanism for regulation of mitochondrial biogenesis through mTORC1-mediated protein translation, and may have direct relevance to the hematological defects associated with mitochondrial diseases and aging. Transcriptional profiling in human primary fetal and adult CD34+ hematopoietic stem/progenitor cells (HSPCs) erythroid progenitor cells (ProEs) by RNA-seq analysis.

2017-05-15 | E-GEOD-74053 | biostudies-arrayexpress

Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A

Project description:Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/CAT1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a post-translational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors by inhibition of deoxyhypusine synthase abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This impacted pathway is critical for eIF5A-regulated erythropoiesis as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins were especially sensitive to the loss of hypusine and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPC, synchronizing mitochondrial metabolism with erythroid differentiation.

2023-01-25 | MSV000091139 | MassIVE

RNA-seq transcriptional profiling in human primary fetal and adult CD34+ hematopoietic stem/progenitor cells (HSPCs) erythroid progenitor cells (ProEs)

2017-05-15 | GSE74053 | GEO

ChIP-seq analysis of H3K27ac in K562 cells with shRNA-mediated depeltion of TFAM expression

Project description:The developing erythroid cells require highly coordinated gene expression and metabolism. By comparing the proteomic and transcriptomic changes in human hematopoietic stem/progenitor cells (HSPCs) and lineage-committed erythroid progenitors (ProEs), and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Two principal mitochondrial factors TFAM and PHB2 are tightly regulated at the protein level and indispensable for mitochondria and erythropoiesis. Depletion of TFAM in erythroid cells alters intracellular metabolism, leading to elevated histone acetylation, deregulated gene expression, defective mitochondria function and erythropoiesis.

2017-05-15 | GSE86864 | GEO

Proteomic analysis of mitochondrial biogenesis in cardiomyocytes differentiated from human induced pluripotent stem cell

Project description:Mitochondria play a crucial role in the differentiation and maturation of human cardiomyocytes (CMs). To identify mitochondrial pathways and regulators that are involved in cardiac differentiation and maturation, we examined human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Proteomic analysis was performed on enriched mitochondrial protein extracts isolated from hiPSC-CMs differentiated from dermal fibroblasts (dFCM) and cardiac fibroblasts (cFCM), at different days of differentiation (between 12 and 115 days), and also from adult and neonatal mouse hearts for comparison. Mitochondrial proteins with a ≥2-fold change between differentiation time points in dFCMs and cFCMs, and between adult versus neonatal mouse hearts, were subjected to Ingenuity Pathway Analysis (IPA), and some upregulated proteins were validated by immunoblotting. The highest significant upregulation was in metabolic pathways for fatty acid oxidation (FAO), the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS) and branched chain amino acid (BCAA) catabolism. The top upstream regulators predicted by IPA were- peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-a), the insulin receptor and the retinoblastoma protein (Rb) transcriptional repressor. In addition, IPA and immunoblotting showed substantial upregulation of the mitochondrial LonP1 protease, which regulates mitochondrial proteostasis, energetics and metabolism. Using this proteomics approach, we have identified key metabolic and intracellular signaling pathways that are up- and down- regulated during the biogenesis of mitochondria in differentiating and maturing cardiac myocytes.

2022-05-19 | PXD014317 | Pride

Investigating B cell stimulation in ubiquilin-1 KO mice

Project description:Ubiquilins are a family of proteins involved in proteasomal degradation of mislocalized membrane proteins. Here, Greer et al. demonstrate that Ubqln1 is required for BCR-driven B cell proliferation through maintenance of protein synthesis following stimulation. In the absence of Ubqln1, mitochondrial proteins accumulate in the cytosol, which may account for the observed proteostasis. BCR stimulation of murine B cells induced a long-lasting mitochondrial depolarization that did not occur in response to LPS. We hypothesize that in the absence of Ubqln1, mitochondrial depolarization leads to an accumulation of mitochondrial membrane proteins in the cytosol, which leads to translational inhibition and a cell cycle block.

2017-11-01 | GSE86113 | GEO

Ubiquilin1 promotes antigen-receptor mediated proliferation by eliminating mislocalized mitochondrial proteins

Project description:Ubiquilins (Ubqlns) are a family of ubiquitin receptors that promote the delivery of hydrophobic and aggregated ubiquitinated proteins to the proteasome for degradation. We carried out a proteomic analysis of a B cell lymphoma-derived cell line, BJAB, that requires UBQLN1 for survival to identify UBQLN1 client proteins. When UBQLN1 expression was acutely inhibited, 120 mitochondrial proteins were enriched in the cytoplasm, suggesting that the accumulation of mitochondrial client proteins in the absence of UBQLN1 is cytostatic. Using a Ubqln1-/- mouse strain, we found that B cell receptor (BCR) ligation of Ubqln1-/- B cells led to a defect in cell cycle entry. As in BJAB cells, mitochondrial proteins accumulated in BCR-stimulated cells, leading to protein synthesis inhibition and cell cycle block. Thus, UBQLN1 plays an important role in clearing mislocalized mitochondrial proteins upon cell stimulation, and its absence leads to suppression of protein synthesis and cell cycle arrest.

2017-09-25 | PXD007610 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data