Hematopoiesis in Murine Fancd2-/- vs WT Fetal Liver
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727546 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14432210_1.fastq.gz | Fastqsanger.gz | |||
| SRR14432210_2.fastq.gz | Fastqsanger.gz | |||
| SRR14432211_1.fastq.gz | Fastqsanger.gz | |||
| SRR14432211_2.fastq.gz | Fastqsanger.gz | |||
| SRR14432212_1.fastq.gz | Fastqsanger.gz |
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Project description:Fanconi anemia (FA) is a rare inherited bone marrow failure (BMF) syndrome, caused by mutation in one of at least 23 proteins in the FA complementation group. The mechanism of BMF in FA is currently unknown. Previous studies have shown that functional defects in hematopoeitic stem and progenitor cells (HSPC) arise spontaneously in response to developmental replication stress in murine FA fetal livers (FL) as early as 13.5 dpc. In this study, we harvested E13.5 wild-type (WT) and Fancd2-/- FL from three pregnancies, depleted samples of erythroid progenitors via FACS against Ter-119, and performed single-cell RNA sequencing. Our goal was to identify which popoulations in the fetal liver at this time point show severe transcriptional dysregulation, as well as to identify what cellular processes in these populations are most affected, in order to gain insight into the mechanism of BMF in FA and guide future studies.
2021-12-31 | GSE173908 | GEO
Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells
2013-06-27 | E-GEOD-46902 | biostudies-arrayexpress
Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population.
2013-06-27 | GSE46902 | GEO
Project description:To investigate the cooperative function of FANCD2/SRSF1 complex in the regulation of R-loops, we performed gene expression, isoform and splicing analysis in Hela cells depleted of SRSF1 or expressing SRSF1 mutants and FA-D2 mutant (FA-D2) and wild type (FA-D2+FANCD2) cells.
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Project description:It is not clear whether disrupted age-specific hematopoiesis contributes to the complex manifestations in leukemia patients who carry identical mutations, particularly in pediatric and adult patients with similar clinical characteristics. By studying a dual-age-specific mouse model, we demonstrate: 1) loss of Pten during the fetal-to-adult hematopoiesis switch (HSC switch) causes sustained fetal hematopoiesis, resulting in death in juvenile leukemia; 2) myeloid-biased hematopoiesis in juvenile mice is associated with the sustained fetal properties of hematopoietic stem cells (HSCs); 3) the age specificity of juvenile myelomonocytic leukemia (JMML) depends on the dosage of Pten and Nf1; 4) single-allelic Pten deletion during the HSC switch causes constitutive activation of mitogen-activated protein kinase (MAPK) in juvenile mice with Nf1 loss of heterozygosity (LOH); and 5) Nf1 LOH causes monocytosis in juvenile mice with Pten haploinsufficiency but does not cause lethality until adulthood. Our data suggest that one copy of Pten is sufficient to maintain an intact negative feedback loop of the Akt pathway and HSC function in reconstitution, despite MAPK being constitutively activated in juvenile mice with Pten+/DNf1LOH. However, two copies of Pten are required to maintain the integrity of the MAPK pathway in juvenile mice with Nf1 haploinsufficiency. Our data indicate that previous investigations of Pten function in wild type mice may not reflect the impact of Pten loss in mice with Nf1 mutations or other genetic defects. We provide a proof-of-concept that disassociated age-specific hematopoiesis contributes to leukemogenesis and pediatric demise.
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Project description:Single-cell multiomics of human fetal hematopoiesis defines a developmental specific population and a fetal signature
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Project description:Oncogene-induced replication stress constitutes an early obstacle for pre-cancerous cells to overcome to progress towards malignancy. Fanconi anaemia signalling represents a major genomic maintenance pathway that is activated in response to replication stress, impinging on stalled replication fork stability and recovery. Here, we report that upon replication stress, phosphorylation of the FANCD2 N-terminus by CHK1 triggers FBXL12-dependent proteasomal degradation of FANCD2, facilitating clearance of FANCD2 at stalled replication forks. This mechanism is required to promote efficient and faithful DNA replication under conditions of CYCLIN E- and drug-induced replication stress. Notably, reconstitution of FANCD2 with mutations in the N-terminal phosphodegron fail to re-establish fork progression in FANCD2-deficient human fibroblasts in response to replication stress. In the absence of FBXL12, FANCD2 becomes trapped on chromatin leading to replication stress, excessive DNA damage, and cell death. In human cancers, FBXL12, CYCLIN E, and Fanconi anaemia signalling are positively correlated and upregulation or amplification of FBXL12 is linked to reduced survival in patients with high CYCLIN E expressing breast tumours. Finally, depletion of FBXL12 exacerbated oncogene-induced replication stress and sensitised breast cancer cells to drug-induced replication stress by WEE1 inhibition. Collectively, our results indicate that FBXL12 constitutes a vulnerability of CYCLIN E-overexpressing cancer cells and may represent a novel target for cancer therapy.
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Project description:Fetal and adult hematopoietic stem and progenitor cells (HSPCs) are characterized by distinct redox homeostasis that may influence their differential cellular behaviour in normal and malignant haematopoiesis. In this work, we have applied a quantitative mass spectrometry-based redox proteomic approach to comprehensively describe reversible cysteine modifications in primary mouse fetal and adult HSPCs. We defined the redox state of 4455 cysteines in fetal and adult HSPCs and demonstrated a higher susceptibility to oxidation of protein thiols in fetal HSPCs. Our data identified ontogenically active redox switches in proteins with a pronounced role in metabolism and protein homeostasis. Additional redox proteomic analysis identified redox switches acting in mitochondrial respiration as well as protein homeostasis to be triggered during onset of MLL-ENL leukemogenesis in fetal HSPCs. Our data has demonstrated that redox signalling contributes to the regulation of fundamental processes of developmental hematopoiesis and has pinpointed potential targetable redox-sensitive proteins in in utero-initiated MLL-rearranged leukaemia. An H9 human embryonic stem cells cell line was applied to validate data from the primary cells.
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Project description:Analysis of FANCD2 targeted sequences and identification DNA motifs regulating transcription of large genes at common fragile sites.
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