Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Role of c-Myc haploinsufficiency in the maintenance of HSCs

ABSTRACT: Here we report a dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/b-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. We showed that c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence, and promoting its apoptosis. We have identified Nr4a1, Nr4a2 and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2 and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediated the function of c-Myc in regulating HSC quiescence while all three genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/b-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induced a blockage of erythroid lineage differentiation through promoting expression and secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc heterozygous mice, and to significantly prolong survival of such mice. Furthermore, we showed that c-Myc mediated Apc loss-induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE156361 | GEO | 2020/08/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

NR4A1 and NR4A2 orphan nuclear receptors regulate endothelial to hematopoietic transition in mouse hematopoietic stem cell specification

Project description:Hematopoietic stem cells (HSCs) sustain life-long hematopoiesis and emerge during mid-gestation from hemogenic endothelial (HE) progenitors via an endothelial to hematopoietic transition (EHT). The full scope of molecular mechanisms governing this process remains unclear. The NR4A subfamily of orphan nuclear receptors act as tumour suppressors in myeloid leukemogenesis and have never been implicated in HSC specification. Here, we report that Nr4a1 and Nr4a2 expression is upregulated in hemogenic endothelium during EHT. Progressive genetic ablation of Nr4a gene dosage results in a gradual decrease in numbers of nascent c-Kit+ hematopoietic progenitors in developing embryos, c-Kit+ cell cluster size in the dorsal aorta, and a block in HSC maturation, revealed by an accumulation of pro-HSCs and pre-HSC-type I cells and decreased numbers of pre-HSC-type II cells. Consistent with these observations, cells isolated from E11.5 Nr4a1-/-; Nr4a2-/- aorta-gonads-mesonephros (AGM) are devoid of in vivo long-term hematopoietic repopulating potential. Molecularly, employing spatial transcriptomic analysis we determined that the genetic ablation of Nr4a1 and Nr4a2 prevents NOTCH signaling from being downregulated in intra-aortic clusters and thus for pro-HSCs to mature into HSCs. Interestingly, this defect is partially rescued via ex vivo culture of dissected AGMs with SCF, IL3 and FLT3L, which may bypass NOTCH-dependent regulation. Overall, our data reveal a novel role for the NR4A family of orphan nuclear receptors in EHT.

2024-11-04 | GSE281058 | GEO

The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS

Project description:Apc, a negative regulator of the canonical Wnt signaling pathway, is a bona-fide tumor suppressor whose loss of function results in intestinal polyposis. APC is located in a commonly deleted region on human chromosome 5q, associated with myelodysplastic syndrome (MDS) suggesting that haploinsufficiency of APC contributes to the MDS phenotype. Analysis of the hematopoietic system of mice with the Apcmin allele that results in a premature stop codon and loss of function, showed no abnormality in steady state hematopoiesis. Bone marrow derived from Apcmin mice showed enhanced repopulation potential, indicating of a cell intrinsic gain of function in the long-term hematopoietic stem cell (HSC) population. However, Apcmin bone marrow was unable to repopulate secondary recipients due to loss of the quiescent HSC population. Apcmin mice developed a myelodysplastic/ myeloproliferative phenotype. Our data indicate that Wnt activation through haploinsufficiency of Apc causes insidious loss of HSC function that is only evident in serial transplantation strategies. These data provide a cautionary note for HSC expansion strategies through Wnt pathway activation, provide evidence that cell extrinsic factors can contribute to the development of myeloid disease and indicate that loss of function of APC may contribute to the phenotype observed in patients with MDS and del(5q). LKS+ cells were isolated from Apcmin or WT mice using high-speed multiparameter flow cytometry. At least 2x104 cells per mouse were isolated with confirmed purity in excess of 90%. The cells were treated with RLT lysis buffer (Qiagen) containing beta-mercaptoethanol to stabilize RNA. RNA was extracted using Qiagen RNeasy Micro Kit according to manufacturers instruction. The RNA was amplified using a linear amplification protocol (Nugen Ovation V2 amplification system). cDNA was fragmented and biotinylated before hybridization onto Affymetrix mouse genome 430 2.0 Array chips

2010-02-21 | E-GEOD-20352 | biostudies-arrayexpress

The Apcmin mouse has altered hematopoietic stem cell function and provides a model for MPD/MDS

2010-02-16 | GSE20352 | GEO

Expression data of mouse hematopoietic cells, Nr4a1/3 wild type and double mutant

Project description:We investigate the cellular and molecular mechanisms of tumor suppression by NR4A1 and NR4A3, and show a cell intrinsic essential function in maintenance of hematopoietic stem cell (HSC) homeostasis. In the absence of Nr4a1/3, HSC lost quiescence, became highly proliferative leukemia-stem cell (LSC) that transplanted AML to recipient mice. We further revealed that loss of NR4A1/3 leads to deregulated expression of the key cell cycle regulator Cdkn1c (P57), c-Myc oncogene, and glucose metabolic genes leading to enhanced aerobic glycolysis or Warburg effect in LSCs. Reintroduction of Nr4a1 in LSCs restored HSC quiescence, and reversed Nr4a1/3 deficiency induced P57 suppression and c-Myc overexpression. Collectively, we identify an essential role of Nr4a1/3 in coordinately regulating cell cycle entry and glucose metabolism to prevent uncontrolled stem cell proliferation and AML transformation. These results have major implications for designing therapeutic strategies in AML. To identify NR4A-dependent molecular signaling pathways that may control HSC homeostasis, we performed genome-wide transcript profiling of Lin-Sca1+ (LS) cells from WT and DKO mice. For Affymetrix analysis, we generated three independent pools of RNA from sorted LS cells from 10-20 WT or DKO (2- to 3-week-old) mice per sample.

2013-12-30 | E-GEOD-31042 | biostudies-arrayexpress

Retinoid X receptor promotes hematopoietic stem cell fitness and quiescence by repressing MYC pathway activation [RXR_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 | GSE199936 | GEO

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

2022-11-16 | GSE199935 | GEO

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

2022-11-16 | GSE199934 | GEO

Expression data of mouse hematopoietic cells, Nr4a1/3 wild type and double mutant

Project description:We investigate the cellular and molecular mechanisms of tumor suppression by NR4A1 and NR4A3, and show a cell intrinsic essential function in maintenance of hematopoietic stem cell (HSC) homeostasis. In the absence of Nr4a1/3, HSC lost quiescence, became highly proliferative leukemia-stem cell (LSC) that transplanted AML to recipient mice. We further revealed that loss of NR4A1/3 leads to deregulated expression of the key cell cycle regulator Cdkn1c (P57), c-Myc oncogene, and glucose metabolic genes leading to enhanced aerobic glycolysis or ‘Warburg effect’ in LSCs. Reintroduction of Nr4a1 in LSCs restored HSC quiescence, and reversed Nr4a1/3 deficiency induced P57 suppression and c-Myc overexpression. Collectively, we identify an essential role of Nr4a1/3 in coordinately regulating cell cycle entry and glucose metabolism to prevent uncontrolled stem cell proliferation and AML transformation. These results have major implications for designing therapeutic strategies in AML.

2013-12-30 | GSE31042 | GEO

Vitamin C dependent KDM6 demethylation specifies a functional chromatin state for endothelial-to-hematopoietic transition [ChIP-Seq]

Project description:Hematopoietic stem/progenitor cells (HSPCs) are generated from hemogenic endothelial cells (HECs) through endothelial-to-hematopoietic transition (EHT); however, the underlying mechanism remains poorly understood. Here, we report that HPC generation is significantly reduced in hPSC differentiatiation in a defined condition without vitamin C (Vc). Mechanistically, the endothelial cells generated in the absence of Vc fail to undergo EHT due to apparent failure in opening genomic loci essential for hematopoiesis. These loci exhibit abnormal accumulation of H3K27me3, a repressive histone modification due to lower activity of its demethylases. Consistently, deletion of H3K27me3 demethylases, JMJD3 and UTX, impaires HPC generation in the presence of Vc. Furthermore, Vc and jmjd3 are also important for HSC generation during zebrafish development. Together, we reveal an obligatory role of Vc underlying EHT process in hematopoisis and further support the important function of Vc during development.

2019-07-22 | GSE132834 | GEO

Vitamin C dependent KDM6 demethylation specifies a functional chromatin state for endothelial-to-hematopoietic transition [RNA-Seq]

2019-07-22 | GSE132969 | GEO