Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

FoxM1 is essential for quiescence and maintenance of hematopoietic stem cell

ABSTRACT: FoxM1, a mammalian Forkhead Box M1 protein, is known as a typical proliferation-associated transcription factor that regulates of G1/S and G2/M transition in the proliferating cells. However, the in vivo function of FoxM1 in adult stem cells remains unknown. Here, we found that FoxM1 is highly expressed in hematopoietic stem cells (HSCs) and is essential for maintaining quiescence and self-renewal of HSCs in vivo. FoxM1-deficient mice developed leukopenia, thrombocytopenia and neutropenia with an approximately 6-fold decrease in HSC pool size, which is associated with a failure of G0 cell cycle regulation and increased cell cycling in HSCs. FoxM1 absence did not affect lineage commitment of HSCs and progenitors. However, FoxM1 loss significantly reduced the repopulating capacity and self-renewal of long-term HSC in a cell-autonomous manner. Mechanistically, FoxM1 loss markedly down-regulates the expression of orphan nuclear receptor Nurr1, known to regulate HSC quiescence. We found that FoxM1 directly bound the promoter region of Nurr1 and induced transcriptional activity of Nurr1 promoter in vitro, and forced expression of Nurr1 rescued FoxM1-deletion-induced G0 loss of HSC-enriched population in vitro. Thus, our studies show a previously unrecognized role of FoxM1 as a critical regulator of HSC quiescence and self-renewal by controlling Nurr1-mediated pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE62360 | GEO | 2015/06/15

SECONDARY ACCESSION(S): PRJNA263909

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

FoxM1 is essential for quiescence and maintenance of hematopoietic stem cell

Project description:FoxM1, a mammalian Forkhead Box M1 protein, is known as a typical proliferation-associated transcription factor that regulates of G1/S and G2/M transition in the proliferating cells. However, the in vivo function of FoxM1 in adult stem cells remains unknown. Here, we found that FoxM1 is highly expressed in hematopoietic stem cells (HSCs) and is essential for maintaining quiescence and self-renewal of HSCs in vivo. FoxM1-deficient mice developed leukopenia, thrombocytopenia and neutropenia with an approximately 6-fold decrease in HSC pool size, which is associated with a failure of G0 cell cycle regulation and increased cell cycling in HSCs. FoxM1 absence did not affect lineage commitment of HSCs and progenitors. However, FoxM1 loss significantly reduced the repopulating capacity and self-renewal of long-term HSC in a cell-autonomous manner. Mechanistically, FoxM1 loss markedly down-regulates the expression of orphan nuclear receptor Nurr1, known to regulate HSC quiescence. We found that FoxM1 directly bound the promoter region of Nurr1 and induced transcriptional activity of Nurr1 promoter in vitro, and forced expression of Nurr1 rescued FoxM1-deletion-induced G0 loss of HSC-enriched population in vitro. Thus, our studies show a previously unrecognized role of FoxM1 as a critical regulator of HSC quiescence and self-renewal by controlling Nurr1-mediated pathways. The Hematopoietic Stem Cells (HSCs) were sorted from FoxM1[fl/fl] and Tie2-Cre FoxM1[fl/fl] mice, then amplified with Ovation Pico WTA System V2 before microarray analysis. There are 3 samples from FoxM1[fl/fl]mice and 3 samples from Tie2-Cre FoxM1[fl/fl] mice.

2015-06-15 | E-GEOD-62360 | biostudies-arrayexpress

Oncogenic Nras has a bimodal effect on hematopoietic stem cells promoting proliferation and self-renewal

Project description:Pre-leukemic mutations are thought to promote clonal expansion of hematopoietic stem cells (HSCs) by increasing self-renewal and competitiveness. However, mutations that increase HSC proliferation tend to reduce competitiveness and self-renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative disease and leukemia. Here we show that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and self-renewal potential upon serial transplantation in irradiated mice, all without immortalizing HSCs or causing leukemia in our experiments. NrasG12D also confers long-term self-renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and self-renewal we assessed HSC cell cycle kinetics using H2B-GFP label retention. We found that NrasG12D had a bimodal effect on HSCs, increasing the proliferation of some HSCs while increasing the quiescence and competitiveness of other HSCs. One signal can therefore increase HSC proliferation, competitiveness, and self-renewal through a bimodal effect that promotes proliferation in some HSCs and quiescence in others. 12 RNA samples from mouse bone marrows were analyzed. There are three biological replicates for each subtype.

2014-03-14 | E-GEOD-45194 | biostudies-arrayexpress

Oncogenic Nras has a bimodal effect on hematopoietic stem cells promoting proliferation and self-renewal

2014-03-14 | GSE45194 | GEO

Tgif1 regulates quiescence and self-renewal signaling pathways of hematopoietic stem cells (HSCs)

Project description:In this study we demonstrate that Tgif1 has a role in HSCs maintenance, self-renewal and quiescence. RNA sequencing data of LSK cells (HSCs enriched cell population) from Tgif1-/- and wild type mice implicates that multiple pathways involved in HSC quiescence and self-renewal are disturbed in Tgif1 deficient mice. RNA expression profiles of wild type (WT) and Tgif1-/- LSK cells were generated by RNA sequencing, in triplicate, using Illumina HiSeq 2000.

2013-09-10 | E-GEOD-50739 | biostudies-arrayexpress

Tgif1 regulates quiescence and self-renewal signaling pathways of hematopoietic stem cells (HSCs)

2013-09-10 | GSE50739 | GEO

Bulk and single cell profiling of CD45+ LSK cells collected from WT and TET2 deficient mice under normoxia and hypoxia (physioxia) conditions (BULK RNA-SEQ)

Project description:Hematopoietic stem cells (HSCs) manifest impaired recovery and self-renewal with a concomitant increase in progenitor content (HPCs) when exposed to ambient air as opposed to physioxia. Mechanisms behind this distinction are poorly understood but have the potential to enhance HSC function for bone marrow transplantation. High resolution transcriptomic analysis revealed that HSCs under physioxia (HSCs- P) upregulate genes involved in self-renewal and quiescence but downregulate genes involved in apoptosis and differentiation compared to HSCs-A. Remarkably, among several genes, Tet2 was significantly downregulated in HSC-Ps compared to HSC-As, which was associated with reduced 5-hydroxymethylcytosine (5-hmC) levels in HSC-Ps. Interestingly, individuals carrying the TET2 mutation in their HSCs are at a higher risk of developing clonal hematopoiesis, myeloid leukemias and cardiovascular disease. Loss of Tet2 in mice results in more HSCs and enhanced self-renewal. TET enzymes are α-ketoglutarate, iron and oxygen-dependent dioxygenases that convert 5-methylcytosine to 5-hydroxymethylcytosine thereby promoting active transcription. We evaluated whether physioxia affects the numbers and function of HSCs and HPCs from Tet2-/- mice similar to wildtype (WT) mice. In contrast to WT-HSCs, we observed complete non-responsiveness of Tet2-/- HSCs to changes in oxygen tension. Tet2-/- HSCs and HPCs exhibited similar numbers and function under physioxia and ambient air. The lack of functional responsiveness to changes in oxygen tension in Tet2-/- HSCs was associated with similar changes in genes involved in self-renewal and quiescence among WT-HSC-Ps, Tet2-/- HSC-Ps and Tet2-/- HSC-As. Our findings define a novel molecular program involving Tet2 in regulating the self-renewal of HSCs under physioxia.

2022-01-07 | GSE192988 | GEO

Bulk and single cell profing of CD45+ LSK cells collected from WT and TET2 deficient mice under normoxia and hypoxia (physioxia) conditions (CITE-SEQ)

2022-01-07 | GSE192992 | GEO

Transcription profiling of mouse long term HSC from control or Pbx1-null mice

Project description:Self-renewal is a defining characteristic of stem cells, however the molecular pathways underlying its regulation are poorly understood. Here we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell cycle regulators, normally expressed in non-self-renewing multipotent progenitors. A significant proportion of Pbx1-dependent genes are associated with the Tgf-b pathway, which serves a major role in maintaining HSC quiescence. Pbx1-deficient LT-HSCs are unable to up-regulate the cyclin dependent kinase inhibitor p57 in response to Tgf-b, providing a mechanism through which Pbx1 maintenance of stem cell self-renewal is achieved. Experiment Overall Design: Highly efficient Pbx1 deletion was induced with poly(I:C) in 3 young MxCre+.Pbx1f/f mutant or 2 MxCre-.Pbx1f/f control mice. LT-HSC (Lin-cKit+Sca1+CD34-CD135-) cells were prospectively sorted from bone marrow of individual mice harvested 4 weeks after the last injection of poly(I:C).

2008-06-20 | E-GEOD-9188 | biostudies-arrayexpress

Transcription profiling of mouse normal LT-HSC vs ST-HSC

Project description:Self-renewal is a defining characteristic of stem cells, however the molecular pathways underlying its regulation are poorly understood. Here we demonstrate that conditional inactivation of the Pbx1 proto-oncogene in the hematopoietic compartment results in a progressive loss of long-term hematopoietic stem cells (LT-HSCs) that is associated with concomitant reduction in their quiescence, leading to a defect in the maintenance of self-renewal as assessed by serial transplantation. Transcriptional profiling revealed that multiple stem cell maintenance factors are perturbed in Pbx1-deficient LT-HSCs, which prematurely express a large subset of genes, including cell cycle regulators, normally expressed in non-self-renewing multipotent progenitors. Experiment Overall Design: LT-HSC (Lin-cKit+Sca1+CD34-CD135-) and ST-HSC (Lin-cKit+Sca1+CD34+CD135-) cells were prospectively sorted from the BM of MxCre-.Pbx1f/f control mice harvested 4 weeks after the last injection of poly(I:C).

2008-06-20 | E-GEOD-9189 | biostudies-arrayexpress

Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence by repressing MYC pathway activation [HISTONE_CnR]

Project description:Hematopoietic stem cells (HSCs) maintain homeostasis and fitness by balancing self-renewal and differentiation. Alterations to the symmetry of HSC divisions reduce quiescence and induce myeloid/megakaryocyte-biased hematopoiesis. Here, we show that HSC self-renewal, fitness, and function are preserved by the master transcription factor retinoid X receptor (RXR). We demonstrate that dual lack of hematopoietic RXRα and RXRβ induces HSC asymmetric cell division resulting in HSC exhaustion and age-associated myeloproliferative disease. Characterization of transcriptomic and epigenetic changes in RXR-deficient HSCs demonstrated chromatin opening, acquisition of a premature aging-like HSC signature, MYC pathway upregulation, and RNA intron retention. Myc haploinsufficiency completely prevents the loss of RXR-deficient HSC activity. Our study unveils the critical relevance of RXR for HSC homeostasis and fitness.

2022-11-16 | GSE199934 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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