Studies in an early development window unveils a severe HSC defect in both murine and human Fanconi anemia [human]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE120168 | GEO | 2018/11/30
REPOSITORIES: GEO
Similar Datasets
Project description:We performed a unique kinetics study of hematopoiesis in Fancg-/- mouse embryos, between E12.5 and E14.5 developmental window. We also report for the first time that a deep HSC defect is also observed during human FA development, and that human FA FL HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg-/- FL HSCs.
2018-11-30 | GSE120167 | GEO
Project description:The Fanconi Anemia (FA) repair pathway governs the repair of highly genotoxic DNA interstrand crosslinks (ICLs) with the assistance of translesion synthesis (TLS), that is facilitated by site-specific monoubiquitination of PCNA (PCNA-Ub) at lysine 164 (K164). Mutation at this residue (K164R) renders mammals hypersensitive to ICLs. Besides the FA pathway, alternative pathways have been associated with ICL repair However, the decision-making between the different pathways remains elusive. To study the dependence and relevance of PCNA-Ub in FA repair and pathway preference, we generated a germline Fancg-/- mouse and intercrossed PcnaK164R/+;Fancg-/+ mice. A compound mutation (KR;FGko) was embryonic lethal with the noted exception of very infrequent escapers. RNAseq of primary double mutant mouse embryonic fibroblasts (MEFs) revealed elevated levels of replication stress-induced checkpoints, which were rescued by Trp53 knockdown. Upon crosslink induction, KR and FGko MEFs displayed a similar phenotype regarding sensitivity, cell cycle arrest, fork progression and accumulation of single stranded DNA.Remarkably, PCNA-Ub excludes the mismatch recognition complex MSH2/MSH6 from being recruited. Our results implicate a dual function of PCNA-Ub in ICL repair: 1. Facilitate TLS opposite the unhooked ICL and 2. simultaneously exclude MSH2/MSH6 recruitment to channel the ICL towards canonical FA repair.
2024-08-09 | PXD035337 | Pride
Project description:Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg-/- mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self-renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg-/- embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg-/- FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology.
| S-EPMC6234961 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-11-30 | GSE120169 | GEO
Project description:Fanconi anemia (FA) is a disorder of genomic instability characterized by progressive bone marrow failure (BMF), developmental abnormalities and an increased susceptibility to cancer. Although various consequences in hematopoietic stem/progenitor cells have been attributed to FA-BMF, the quest to identify the initial pathological event is still ongoing. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts of six FA patients with FANCA mutations. An improved reprogramming method yielded iPSC-like colonies from all patients, and iPSC clones were propagated from two patients. Quantitative evaluation of the differentiation ability demonstrated that the differentiation propensity toward the hematopoietic and endothelial lineages is already defective in early hemoangiogenic progenitors. The expression levels of critical transcription factors were significantly downregulated in these progenitors. These data indicate that the hematopoietic consequences in FA patients originate from the early hematopoietic stage, and highlight the potential usefulness of iPSC technology for elucidating the pathogenesis of FA-BMF.
2015-02-03 | GSE65507 | GEO
Project description:Fanconi anemia (FA) is a disorder of genomic instability characterized by progressive bone marrow failure (BMF), developmental abnormalities and an increased susceptibility to cancer. Although various consequences in hematopoietic stem/progenitor cells have been attributed to FA-BMF, the quest to identify the initial pathological event is still ongoing. To address this issue, we established induced pluripotent stem cells (iPSCs) from fibroblasts of six FA patients with FANCA mutations. An improved reprogramming method yielded iPSC-like colonies from all patients, and iPSC clones were propagated from two patients. Quantitative evaluation of the differentiation ability demonstrated that the differentiation propensity toward the hematopoietic and endothelial lineages is already defective in early hemoangiogenic progenitors. The expression levels of critical transcription factors were significantly downregulated in these progenitors. These data indicate that the hematopoietic consequences in FA patients originate from the early hematopoietic stage, and highlight the potential usefulness of iPSC technology for elucidating the pathogenesis of FA-BMF. The investigation of the RNA-seq analysis of iPSC-derived HAPCs.
2015-02-03 | E-GEOD-65507 | biostudies-arrayexpress
Project description:We profiled primary HSPCs from Fanconi anemia (FA) patients for single cell transcriptome (scRNA-seq) to identify additional determinants of HSPC impairment leading to the bone marrow failure,. Trajectory analysis revealed that early hematopoietic differentiation potential is preserved in FA HSPCs. As expected, p53 and TGFβ pathway genes were overexpressed in HSPCs from FA patients. The oncogene MYC was also identified as one of the top over-expressed genes in FA HSPCs. Interestingly, we observed co-existence of “High-TP53” expressing HSPCs and HighMYC expressing HSPCs in FA bone marrow. Inhibition of MYC expression by the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of primary HSPCs from FA patients but rescued the physiological/genotoxic stress in HSPCs from FA mice. The “High-MYC” expressing HSPCs exhibited a significant downregulation of cell adhesion genes, such as CXCR4. Consistently, HSPCs in FA patients showed a defect in adhesion to their bone marrow niche resulting in egression from the bone marrow into peripheral blood. We speculate that MYC overexpression impairs HSPC function and contributes to exhaustion of HSPCs in FA bone marrow.
2020-09-08 | GSE157591 | GEO
Project description:Fanconi anemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink (ICL) repair resulting in chromosome breakage. The FA repair pathway protects against carcinogenic endogenous and exogenous aldehydes. Individuals with FA are hundreds to thousands-fold more likely to develop head and neck (HNSCC), esophageal and anogenital squamous cell carcinomas (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or human papillomavirus (HPV) infection. Here, by sequencing FA SCCs, we demonstrate that the primary genomic signature of FA-deficiency is the presence of high numbers of structural variants (SVs). SVs are enriched for small deletions, unbalanced translocations, and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not HPV infection, and lead to somatic copy number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte intrinsic inflammatory signaling, which would contribute to the aggressive nature of FA SCCs. We propose that genomic instability in sporadic HPV-negative HNSCC may arise consequent to the FA repair pathway being overwhelmed by ICL damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA crosslinking damage.
2022-09-04 | GSE195811 | GEO
Project description:Prostate cancer is one of the leading causes of death among men worldwide and thus research on the genetic factors enabling the formation of treatment resistant cancer cells is crucial for improving patient outcomes.Here, we report a cell-line specific dependence on FANCI and related signalling pathways to counteract effects of DNA damaging chemotherapy in prostate cancer. Our results reveal that FANCI depletion results in significant downregulation of Fanconi anemia (FA) pathway members in prostate cancer cells indicating that FANCI is an important regulator of FA pathway. Furthermore, we found that FANCI silencing reduces proliferation in p53-expressing prostate cancer cells. This extends the evidence that inactivation of FANCI may convert cancer cells from a resistant to an eradicable state under the stress of DNA-damaging chemotherapy. Our results also indicate that high expression of FA pathway genes correlates with poorer survival in prostate cancer patients. Moreover, genomic alterations of FA pathway members are prevalent in prostate adenocarcinoma patients; mutation and copy number information for the FA pathway genes in seven patient cohorts (N = 1732 total tumor samples) reveals that 1025 (59.2%) tumor samples have an alteration in at least one of the FA pathway genes, suggesting that genomic alteration of the pathway is a prominent feature in patients with the disease.
2023-09-29 | GSE211363 | GEO
Project description:To elucidate the transcriptional and epigenetic alterations underlying the neurogenic defects of FA-NSCs, we conducted gene expression microarray analysis and global DNA methylation profiling. The gene expression pattern of gene-corrected NSCs (C-FA-NSCs) resembled that of control-NSCs but clustered distantly from FA-NSCs (Fig. 6F and Table S1). Hierarchical clustering based on DNA methylation levels in the promoter region (+/-1.5kb from TSS) of genes whose expression levels were rescued in C-FA-NSCs, placed C-FA-NSCs closer to control-NSCs and away from FA-NSCs (Fig. 6G), although this pattern was not seen at the whole genome level (Fig. S4C). This suggests that FANCA gene correction leads to specific methylation changes in a subset of promoters.
2014-05-15 | GSE57685 | GEO