Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Phospholipase Cγ1 is crucially required for EpoR/JAK2 controlled erythropoietic differentiation.

ABSTRACT: Erythropoiesis is a multi-step process in which the development of red blood cells occurs through expansion and differentiation of hematopoietic stem cells (HSCs) into more committed progenitors. In vivo and in vitro studies have pointed out the major role of proximal erythropoietin receptor (EpoR) signaling through JAK2 tyrosine-kinase as a central regulator of erythropoiesis 1,2. However, little is known on more distant signalling pathways driving EPO/JAK2-induced differentiation of erythroid progenitors. Here, we demonstrate that phospholipase Cγ 1 (PLCγ1) is activated downstream of EpoR/JAK2 and is crucially required for differentiation of erythroid progenitor cells. In the absence of PLCγ1, erythroid progenitors exhibited dramatically impaired differentiation and colony-forming potential. To identify PLCγ1 effector molecules involved in regulation of erythroid differentiation we performed global gene expression and methylome analysis. In PLCγ1-deficient erythroid progenitors, profound changes in the landscape of DNA methylation and gene expression were observed. Taken together, our findings identify PLCγ1 as a central regulator in erythroid development and highlight its physiological relevance in development and maintenance of normal hematopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE54223 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA235958

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Epo-Induced Erythroid Maturation Is Dependent on Plcγ1 Signaling

Project description:Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells into more committed progenitors and finally into erythrocytes. Binding of erythropoietin to its receptor (EpoR) is strictly required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Jak2 tyrosine-kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (Plcγ1) is activated downstream of EpoR/Jak2 independently of Stat5. Plcγ1-deficient proerythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of Plcγ1 in immunophenotypically defined hematopoietic stem cells (Lin-Sca1+KIT+CD48-CD150+) severely reduced erythroid development. To identify Plcγ1 effector molecules involved in regulation of erythroid differentiation we assessed for changes on the level of transcription and DNA methylation after inactivation of Plcγ1. The single common downstream effector was H2AFY2, which encodes for the histone variant macroH2A2 (mH2A2). Suppression of macroH2A2 expression recapitulated the effects of Plcγ1 knockdown on erythroid maturation. Taken together, our findings identify Plcγ1 and its downstream target macroH2A2, as a “non-canonical” signaling pathway essential for erythroid differentiation.

2015-12-31 | GSE60087 | GEO

Epo-Induced Erythroid Maturation Is Dependent on PlcÎ³1 Signaling

Project description:Erythropoiesis is a tightly regulated process. Development of red blood cells occurs through differentiation of hematopoietic stem cells into more committed progenitors and finally into erythrocytes. Binding of erythropoietin to its receptor (EpoR) is strictly required for erythropoiesis as it promotes survival and late maturation of erythroid progenitors. In vivo and in vitro studies have highlighted the requirement of EpoR signaling through Jak2 tyrosine-kinase and Stat5a/b as a central pathway. Here, we demonstrate that phospholipase C gamma 1 (PlcÎ³1) is activated downstream of EpoR/Jak2 independently of Stat5. PlcÎ³1-deficient proerythroblasts and erythroid progenitors exhibited strong impairment in differentiation and colony-forming potential. In vivo, suppression of PlcÎ³1 in immunophenotypically defined hematopoietic stem cells (Lin-Sca1+KIT+CD48-CD150+) severely reduced erythroid development. To identify PlcÎ³1 effector molecules involved in regulation of erythroid differentiation we assessed for changes on the level of transcription and DNA methylation after inactivation of PlcÎ³1. The single common downstream effector was H2AFY2, which encodes for the histone variant macroH2A2 (mH2A2). Suppression of macroH2A2 expression recapitulated the effects of PlcÎ³1 knockdown on erythroid maturation. Taken together, our findings identify PlcÎ³1 and its downstream target macroH2A2, as a ânon-canonicalâ signaling pathway essential for erythroid differentiation. MCIP-seq was used to interrogate methylation changes during Epo-induced differentiation of murine I/11 erythroblastic cell line upon knock-down of Plcy1 as compared to a mock control. Two different shRNA constructs that target Plcg1 were investigated at two different time points.

2015-12-31 | E-GEOD-60087 | biostudies-arrayexpress

Effect of erythropoietin on the gene expression of Xenopus tropicalis peripheral blood cells.

Project description:The regulatory system of erythropoiesis through erythropoietin (EPO) and its receptor (EPOR) is essential for vertebrates' life. In humans, EPO affects the erythroid progenitors and stimulates proliferation and differentiation. The EPO-EPOR axis is mainly mediated by the JAK2-STAT5 pathway. After terminal maturation, erythrocytes lost EPOR expression; however, erythrocytes of amphibian Xenopus tropicalis maintain EPOR expression even after their terminal maturation. Because erythrocytes of vertebrates except for adult mammals are nucleated, we hypothesized that EPO can alter its transcriptional state. To explore the effects of EPO on Xenopus mature erythrocytes, we performed RNA-Seq analysis on EPO-stimulated Xenopus peripheral blood cells. The EPO-stimulated group showed increased expression of direct target genes of STAT such as cish, socs3, and socs1 indicating a functional signal transduction system. Furthermore, we observed several EPO-responsive genes that were not reported in mammalian erythroid progenitors. These findings suggest the functional difference between enucleated erythrocytes in adult mammals and nucleated erythrocytes in fetal mammals and non-mammalian vertebrates.

2024-04-05 | GSE251901 | GEO

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

Transcriptome analysis of erythroblastic island macrophages

Project description:The erythroblastic island (EBI), composed of a central macrophage and surrounding erythroid cells, was the first hematopoietic niche discovered. The identity of EBI macrophages has thus far remained elusive. Gene expression profiles of BM F4/80+Epor-eGFP+ macrophages suggest a specialized function in supporting erythropoiesis.

2019-05-31 | GSE127980 | GEO

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

Global gene expression prolife of primary cultured murine stress erythroid progenitors.

Project description:Inflammation inhibits steady state erythropoiesis, while at the same time it induces stress erythropoiesis to maintain erythroid homeostasis. Stress erythropoiesis relies on the rapid expansion of early progenitors that do not differentiate until the increase in serum Epo promotes a transition in progenitors to enable their synchronous differentiation. RNA-seq analysis allows us to identify an inflammatory transcriptome signature in early progenitors that induces iNOS-derived NO production. The accumulation of NO establishes a metabolism that promotes cell proliferation while inhibiting the differentiation of early progenitors. In contrast, the transition of progenitors to differentiation is marked by the suppressed inflammatory responses and a consequent decrease of iNOS-derived NO. We show that Epo initiates this transition response by altering progenitor metabolism to support itaconate production, resulting in the activation of Nrf2 that suppresses the inflammatory responses, which in turn alleviates the NO-mediated inhibition of erythroid program. Consequent differentiation of stress erythroid progenitors generates a bolus of new erythrocytes to maintain erythroid homeostasis until steady state erythropoiesis can resume.

2023-12-31 | GSE190030 | GEO

miRNA profiling in Human K562 cells undergoing erythropoietic induction

Project description:We investigated the miRNA expression in ex vivo human erythroid cultures from K562 cells. Hypothetically, the decline of certain miRNAs may promote erythropoiesis by unblocking expression of key functional proteins while the up-regulation of other miRNAs may block commitment to non-erythroid lineages. By comparison with the miRNA expression changes in human umbilical cord blood-derived CD34 cells, signature miRNAs for erythroid development can be discovered. Keywords: miRNA expression profiling

2007-04-01 | GSE6001 | GEO

RNA-seq transcriptonal profiling in E13.5 fetal liver erythroid cells from Tfam WT and KO mice

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. To determine the role of TFAM in mitochondrial function during erythroid development, we generated Tfam conditional knockout (KO) mice by an erythroid-specific EpoR-Cre allele. We isolated the CD71+Ter119+ embryonic day (E)13.5 fetal liver erythroid cells by FACS sorting, and performed RNA-seq transcriptional profiling analysis.

2017-05-15 | GSE86865 | GEO

Distinct contributions of KAT2A histone acetyl-transferase complexes to human erythropoiesis [RNA-seq]

Project description:KAT2A is a histone acetyl-transferase involved in stabilization of transcriptional activity through acetylation of lysine residue 9 of Histone 3. Mouse knockout models suggest that Kat2a is dispensable for haematopoietic stem and progenitor cell activity, despite a central role in survival and maintenance of Acute Myekoid Leukaemia cells through block of differentiation. Herein, we investigate KAT2A activity in human cord blood haematopoiesis and identify a specific requirement in the establishment of the erythroid lineage. KAT2A is required for specification and survival of Erythroid-Megakaryocytic progenitors, with regulation of expression of the erythropoietin receptor (EPOR) gene, which participates in lineage commitment, as well as of later effector genes in the platelet and erythroid lineages. Early and late lineage roles can be distinctly attributed to the ATAC and SAGA complexes in which context KAT2A exerts its activity. ATAC is active earlier in erythroid lineage development and mediates MEP specification from HSC, whilst SAGA activity is required post-commitment, including in expression of haemoglobin genes. We thus position KAT2A as a novel regulator of human erythropoiesis and separate early and later effects in lineage development with complex specificity. This has implications for putative therapeutic targeting of KAT2A complexes in leukaemia.

2021-09-28 | GSE128902 | GEO

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