Role of c-Myc haploinsufficiency in the maintenance of HSCs
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ABSTRACT:
PROVIDER: PRJNA657604 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12462988.fastq.gz | Fastqsanger.gz | |||
| SRR12462989.fastq.gz | Fastqsanger.gz | |||
| SRR12462990.fastq.gz | Fastqsanger.gz | |||
| SRR12462991.fastq.gz | Fastqsanger.gz | |||
| SRR12462992.fastq.gz | Fastqsanger.gz |
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Project description: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.
2020-08-18 | GSE156361 | GEO
Project description:This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/β-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting 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 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 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/β-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting 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 the survival of those 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.
| S-EPMC8215193 | biostudies-literature
Project description:Analysis of HSCs from control and c-myc N-myc deficient long-term hematopoietic stem cells. HSCs lacking both c-myc and N-myc display increased apoptosis rates. Data provide insight into the molecular changes occuring upon complete loss of Myc activity, clarifying the resulting apoptotic mechanism and the role of Myc family proteins in HSCs. LT-HSC (Lin-Sca1+CD150+CD48-) cells were sorted from the BM of MxCre c-myc flox2 N-myc flox2 (experimental) and c-myc flox2 N-myc flox2 (control) mice 3 days after the last pI-pC injection. Each condition was analysed in triplicates, with each replicate consisting of a pool of 3 dKO mice or 2 control mice.
2009-02-20 | E-GEOD-12467 | biostudies-arrayexpress
Project description:Analysis of HSCs from control and c-myc N-myc deficient long-term hematopoietic stem cells. HSCs lacking both c-myc and N-myc display increased apoptosis rates. Data provide insight into the molecular changes occuring upon complete loss of Myc activity, clarifying the resulting apoptotic mechanism and the role of Myc family proteins in HSCs.
2009-02-20 | GSE12467 | GEO
Project description:Recent years have seen exploration into the hematopoietic stem cell (HSC) niche in adult bone marrow (BM). Due to their relatively rare occurrence, research on splenic HSCs and their role in hematopoiesis under steady-state conditions has been limited. However, studies have been taken up to understand extramedullary hematopoiesis (EMH) in spleen under stress and pathological conditions. Moreover, activation of EMH also has been linked to mobilized BM derived HSCs, and contribution from the splenic HSCs has not been clear. Our studies have identified a myofibroblastic niche in spleen that supports HSCs under homeostatic conditions. To assess the maintenance and regulation of HSCs in spleen tissue by niche cells, we performed label-free mass spectrometry (MS) based quantitative proteomic analysis. The splenic HSC niche cells including capsular and trabecular myofibroblasts (or CTMs/TBs), Lin-CD45- stromal cell population (or STs) and HSPCs (Lin-CD45+c-kit+Sca-1+) were isolated by fluorescence-activated cell sorting (FACS). The sorted cells were then lysed in lysis buffer, sonicated, thermally denatured, reduced, alkylated and tryptic digests were processed, desalted and analyzed on nano-LC coupled with high resolution mass spectrometer. Using Proteome Discoverer program and computational analysis performed on the global protein expression we examined the protein-protein interactions, cell-cell interactions and molecular pathways enriched in each cell population. This study demonstrates the molecular components HSC niche and presents a model to uncover novel hematopoietic regulators crucial for improving the function of adult and pluripotent stem cell derived HSCs.
2024-07-18 | MSV000095385 | MassIVE
Project description:Analysis of HSCs from control and c-myc N-myc deficient long-term hematopoietic stem cells. HSCs lacking both c-myc and N-myc display increased apoptosis rates. Data provide insight into the molecular changes occuring upon complete loss of Myc activity, clarifying the resulting apoptotic mechanism and the role of Myc family proteins in HSCs and commited progenitors.
2009-02-20 | GSE12536 | GEO
Project description:Clonal hematopoiesis plays a critical role in the initiation and development of hematologic malignant diseases. FOXM1, a well-known transcription factor, is often downregulated in CD34+ cells from patients with del(5q) Myelodysplastic Syndrome (MDS). Here we show that Foxm1 haploinsufficiency disturbs normal hematopoiesis and confers a competitive repopulation advantage to hematopoietic stem cells (HSCs) for a short period, but disrupts the long-term self-renewal capacity of HSCs, recapitulating the phenotypes of abnormal HSCs in MDS patients. Moreover, heterozygous inactivation of Foxm1 leads to an increase in DNA damage in hematopoietic stem/progenitor cells (HSPCs). Foxm1 haploinsufficiency induces an MDS-like disease in a mouse model with LPS-induced chronic inflammation, and accelerates AML-ETO9a-mediated leukemogenesis. We also identified PARP1, an important enzyme responding to various kinds of DNA lesions, as a previously unrecognized target of Foxm1. Foxm1 haploinsufficiency inhibits DNA damage response (DDR) in HSCs by downregulating PARP1 expression in HSPCs. Given that PARP1 inhibitors increase the risk of MDS and AML in clinical therapy for solid tumors, our results suggest that downregulation of the Foxm1-PARP1 molecular axis plays a pivotal role in the pathogenesis of MDS by promoting clonal hematopoiesis and reducing genome stability.
2022-08-10 | GSE208564 | GEO
Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs In order to understanding the transcription regulation network downstream of Brg1 in murine AML, we performed microarray in murine MLL-AF9/NrasG12D cell line under the condition that Brg1 was suppressed by three independent shRNAs for 96h.
2013-12-02 | E-GEOD-52231 | biostudies-arrayexpress
Project description:Cancer cells frequently depend on chromatin regulatory activities to maintain a malignant phenotype. Here, we show that leukemia cells require the mammalian SWI/SNF chromatin remodeling complex for their survival and aberrant self-renewal potential. While Brg1, an ATPase subunit of SWI/SNF, is known to suppress tumor formation in several cancer types, we found that leukemia cells instead rely on Brg1 to support their oncogenic transcriptional program, which includes Myc as one of its key targets. To account for this context-specific function, we identify a cluster of lineage-specific enhancers located 1.7 megabases downstream of Myc that are occupied by SWI/SNF, as well as the BET protein Brd4. Brg1 is required at these distal elements to maintain transcription factor occupancy and for long-range chromatin looping interactions with the Myc promoter. Notably, these distal Myc enhancers coincide with a region that is focally amplified in 3% of acute myeloid leukemia. Together, these findings define a leukemia maintenance function for SWI/SNF that is linked to enhancer-mediated gene regulation, providing general insights into how cancer cells exploit transcriptional coactivators to maintain oncogenic gene expression programs Enhancer usually regulates its targets through physical contact/interaction. In order to study chromosome conformation of Myc locus and potential distal enhancer E1-E5 region in murine AML cells, we utilize the high resolution 4C-seq and analysis pipeline to search cis elements that physical interact with Myc and E1-E5 region through setting up two individual viewpoints in these two regions.
2013-12-02 | E-GEOD-52595 | biostudies-arrayexpress
Project description:Clinical GATA2 deficiency syndromes arise from germline haploinsufficiency inducing mutations in GATA2, resulting in immunodeficiency that evolves to myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). How GATA2 haploinsufficiency disrupts the function and transcriptional network of hematopoietic stem/progenitors (HSCs/HSPCs) to facilitate the shift from immunodeficiency sequalae to pre-leukemia is poorly characterised. Using a conditional mouse model harboring a single allele deletion of Gata2 when HSCs emerge in utero, we identify pervasive defects in HSPC differentiation from young adult Gata2 haploinsufficient mice during B-cell maturation, early erythroid specification, megakaryocyte maturation to platelets and inflammatory cell generation. Gata2 haploinsufficiency abolishes HSC self-renewal and multi-lineage differentiation capacity following transplantation. These alterations closely associate with deregulated DNA damage responses and inflammatory signalling conveyed from Gata2 haploinsufficient HSCs. We also identify functional interplay between Gata2 and Asxl1, a driver of DNA damage and inflammation and, notably, a recurrent secondary mutation found in GATA2 haploinsufficiency disease progression to MDS/AML. shRNA mediated knockdown of Asxl1 in Gata2 haploinsufficient HSPCs led to a differentiation block in committed progenitor formation beyond that in Gata2 haploinsufficient HSPCs. By analysis of HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice, we discover hyperproliferation of double haploinsufficent HSCs, which are also functionally compromised in transplantation compared to their single haploinsufficient counterparts. Through both Gata2/Asxl1 dependent and unique transcriptional programs, HSCs from young adult compound Gata2/Asxl1 haploinsufficient mice fortify deregulated DNA damage responses and inflammatory signalling in HSCs initiated in Gata2 haploinsufficient mice and establish a broad pre-leukemic program. Our data reveal how Gata2 haploinsufficiency initially drives deregulation of HSC genome integrity and suggest the mechanisms of how secondary mutations like ASXL1 take advantage of HSC genomic instability to nurture a pre-leukemic state in GATA2 haploinsufficiency syndromes.
2025-08-27 | GSE283398 | GEO