Redox-Dependent Igfbp2 Signaling Controls Brca1 DNA Damage Response to Govern Neural Stem Cell Fate
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PROVIDER: PRJNA916906 | ENA |
REPOSITORIES: ENA
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Project description:Neural stem cell (NSC) maintenance and functions are regulated by reactive oxygen species (ROS). However, the mechanisms by which ROS control NSC behavior remain unclear. Here we report that ROS-dependent Igfbp2 signaling controls DNA repair pathways which balance NSC self-renewal and lineage commitment. Ncf1 or Igfbp2 deficiency constrained NSCs to a self-renewing state and prevented neurosphere formation due to absent Igfbp2 cysteine-43 oxidation. Ncf1-dependent oxidation of Igfbp2 promoted neurogenesis by NSCs in vitro and in vivo, while repressing Brca1 DNA damage response genes and inducing DNA double-strand breaks (DDSBs). By contrast, Ncf1–/– and Igfbp2–/– NSCs favored the formation of oligodendrocytes in vitro and in vivo. Notably, transient repression of Brca1 DNA repair pathway genes induced DDSBs and was sufficient to rescue the ability of Ncf1–/– and Igfbp2–/– NSCs to lineage-commit to form neurospheres and neurons. Our study highlights the role of DNA damage/repair in orchestrating NSC fate decisions downstream of redox-regulated Igfbp2.
2023-01-17 | GSE221955 | GEO
Project description:Neural stem cell (NSC) maintenance and functions are regulated by reactive oxygen species (ROS). However, the mechanisms by which ROS control NSC behavior remain unclear. Here we report that ROS-dependent Igfbp2 signaling controls DNA repair pathways which balance NSC self-renewal and lineage commitment. Ncf1 or Igfbp2 deficiency constrains NSCs to a self-renewing state and prevents neurosphere formation. Ncf1-dependent oxidation of Igfbp2 promotes neurogenesis by NSCs in vitro and in vivo while repressing Brca1 DNA damage response genes and inducing DNA double-strand breaks (DDSBs). By contrast, Ncf1-/- and Igfbp2-/- NSCs favor the formation of oligodendrocytes in vitro and in vivo. Notably, transient repression of Brca1 DNA repair pathway genes induces DDSBs and is sufficient to rescue the ability of Ncf1-/- and Igfbp2-/- NSCs to lineage-commit to form neurospheres and neurons. NSC lineage commitment is dependent on the oxidizable cysteine-43 residue of Igfbp2. Our study highlights the role of DNA damage/repair in orchestrating NSC fate decisions downstream of redox-regulated Igfbp2.
| S-EPMC9883463 | biostudies-literature
Project description:How cellular diversity is created is a key question in biology. Embryonic stem cells (ESCs) are pluripotent cells that can develop into any cell type in the body. Yet, the regulatory mechanisms that govern cell fate decisions remain largely unknown. Moreover, although genetically identical, individual ESCs are strikingly heterogeneous regarding their differentiation capacity but the molecular basis for this phenotypic heterogeneity is unclear. We now demonstrate that pluripotent mouse ESCs (mESCs) display large natural variations in mitochondrial reactive oxygen species (ROS) levels that individualize their nuclear redox state and redox-sensitive H3K4me3 landscape. By using intracellular redox probes, we sorted pluripotent and differentiating mESCs based on their nuclear redox environments into subpopulations and analysed their differentiation capacity. We show that more reduced mESCs are biased towards the mesendodermal fate and form the primitive streak upon differentiation. This mesendodermal specification is due to increased Wnt signaling pathway activity, mediated via a ROS-specific regulatory mechanism of p53-dependent expression of the Wnt ligand Wnt3, and increased H3K4me3 levels. We demonstrate that formation of a primitive streak-like structure by differentiating mESCs is initiated by increased mitochondrial ROS and p53 stabilization, followed by antioxidant Nrf2 response pathway activation that leads to a reduced nuclear redox environment, allowing for the accumulation of ROS-sensitive H3K4me3 marks and activation of Wnt3 and other mesendoderm-related gene expression. In summary, our study shows that natural variations in endogenous ROS levels individualize the H3K4me3 landscape of mESCs, and through gene expression changes govern their cell fate decision at the onset of gastrulation.
2024-07-07 | GSE244779 | GEO
Project description:How cellular diversity is created is a key question in biology. Embryonic stem cells (ESCs) are pluripotent cells that can develop into any cell type in the body. Yet, the regulatory mechanisms that govern cell fate decisions remain largely unknown. Moreover, although genetically identical, individual ESCs are strikingly heterogeneous regarding their differentiation capacity but the molecular basis for this phenotypic heterogeneity is unclear. We now demonstrate that pluripotent mouse ESCs (mESCs) display large natural variations in mitochondrial reactive oxygen species (ROS) levels that individualize their nuclear redox state and redox-sensitive H3K4me3 landscape. By using intracellular redox probes, we sorted pluripotent and differentiating mESCs based on their nuclear redox environments into subpopulations and analysed their differentiation capacity. We show that more reduced mESCs are biased towards the mesendodermal fate and form the primitive streak upon differentiation. This mesendodermal specification is due to increased Wnt signaling pathway activity, mediated via a ROS-specific regulatory mechanism of p53-dependent expression of the Wnt ligand Wnt3, and increased H3K4me3 levels. We demonstrate that formation of a primitive streak-like structure by differentiating mESCs is initiated by increased mitochondrial ROS and p53 stabilization, followed by antioxidant Nrf2 response pathway activation that leads to a reduced nuclear redox environment, allowing for the accumulation of ROS-sensitive H3K4me3 marks and activation of Wnt3 and other mesendoderm-related gene expression. In summary, our study shows that natural variations in endogenous ROS levels individualize the H3K4me3 landscape of mESCs, and through gene expression changes govern their cell fate decision at the onset of gastrulation.
2024-07-07 | GSE244777 | GEO
Project description:Rhabdomyosarcoma (RMS) is the most common childhood sarcoma and is identified as either the embryonal or alveolar (ARMS) subtype. In approximately 75% of cases, ARMSs are characterized by specific chromosomal translocations that involve PAX and FKHR genes. ARMS gene expression signatures vary, depending on the presence or absence of the translocations. Insulin-like growth factor-binding protein 2 (IGFBP2) is strongly overexpressed in translocation-negative RMS. Because IGFBP2 is associated with tumorigenesis, we investigated its functional role in RMS. An analysis of IGFBP2 distribution in RMS cell lines revealed a strong accumulation in the Golgi complex, in which morphological characteristics appeared peculiarly modified. After silencing IGFBP2 expression, our microarray analysis revealed mostly cell cycle and actin cytoskeleton gene modulations. In parallel, IGFBP2-silenced cells showed reduced cell cycle and rates of invasion and decreased seeding in the lungs after tail vein injections in immunodeficient mice. An analysis of IGFBP2 mRNA and protein localization in human tumors showed abnormal protein accumulation in the Golgi complex, mostly in PAX/FKHR-negative RMS. Moreover, an analysis of patients with RMS revealed the presence of conspicuous circulating levels of IGFBP2 proteins in children with highly aggressive RMS tumors. Taken together, our data provide evidence that IGFBP2 contributes to tumor progression and that it could be used as a marker to better classify clinical and biological risks in RMS. Three independent silencing experiments on RH36, an embryonal rhabdomyosarcoma cell line, were performed to study the role of IGFBP2 oncogene in this childhood tumor. Each of 3 biological replicates has its own control which is represented by cell culture treated with a non-targeting siRNA (siCONTROL). 3 controls were used to produce a M-bM-^@M-^\control poolM-bM-^@M-^] that has been used as reference in all microarray experiments. Each microarray experiment consists of a competitive hybridization between test and reference RNA (e.g. silenced cells vs. control), labelled with Cy3 or Cy5. Two microarray experiments were performed for each of three silencing experiment (technical replicate). Each slide was scanned and the data was normalized and analyzed.
2011-12-05 | E-GEOD-23196 | biostudies-arrayexpress
Project description:Rhabdomyosarcoma (RMS) is the most common childhood sarcoma and is identified as either the embryonal or alveolar (ARMS) subtype. In approximately 75% of cases, ARMSs are characterized by specific chromosomal translocations that involve PAX and FKHR genes. ARMS gene expression signatures vary, depending on the presence or absence of the translocations. Insulin-like growth factor-binding protein 2 (IGFBP2) is strongly overexpressed in translocation-negative RMS. Because IGFBP2 is associated with tumorigenesis, we investigated its functional role in RMS. An analysis of IGFBP2 distribution in RMS cell lines revealed a strong accumulation in the Golgi complex, in which morphological characteristics appeared peculiarly modified. After silencing IGFBP2 expression, our microarray analysis revealed mostly cell cycle and actin cytoskeleton gene modulations. In parallel, IGFBP2-silenced cells showed reduced cell cycle and rates of invasion and decreased seeding in the lungs after tail vein injections in immunodeficient mice. An analysis of IGFBP2 mRNA and protein localization in human tumors showed abnormal protein accumulation in the Golgi complex, mostly in PAX/FKHR-negative RMS. Moreover, an analysis of patients with RMS revealed the presence of conspicuous circulating levels of IGFBP2 proteins in children with highly aggressive RMS tumors. Taken together, our data provide evidence that IGFBP2 contributes to tumor progression and that it could be used as a marker to better classify clinical and biological risks in RMS.
2011-12-05 | GSE23196 | GEO
Project description:Background and aim: The Insulin-like growth factor (IGF) axis is increasingly suggested to be involved in fatty liver disease and progression. We identified IGFBP2 as transcriptional regulatory effect network in liver steatosis and conducted a translational approach of its role in liver pathology from mouse to human, and whether it is influenced by conventional clinical intervention that mitigate hepatic steatosis. Methods: Primary hepatocytes from either C57Bl6 controls, alb-SREBP-1c mice with moderate transgene induced hepatic lipid accumulation or aP2-SREBP-1c mice with massive ectopic hepatic lipid accumulation, were analyzed to identify regulatory networks based on differentially regulated hepatic gene expression. In a translational approach, serum of morbidly obese patients with and without diabetes and biopsy-proven NAFLD were used for ELISA-based validation of mouse data. Moreover, sera of patients undergoing intervention were analyzed and correlated to liver fat content. Results: Comparative knowledge-based transcriptome analysis identified IGFBP2 as top score regulatory effect network between moderate and aggravated fatty liver in mouse models. The reduced expression of IGFBP2 in aP2-SREPB-1c progressed fatty liver associated with Igfbp2 promoter hypermethylation. Reduced secretion of IGFBP2 from aP2-SREBP-1c hepatocytes was reflected in the circulation of the animals. In this phenotype, reductions of IGFBP2 were accompanied by reduced fatty acid oxidation and increased methyltransferase and SIRT activity. Physiologically, IGFBP2 has no direct impact on lipid metabolism but might modulate IGF1 action on de novo lipogenesis. In humans, IGFBP2 levels declined from non-obese men to morbidly obese men with NAFLD and NASH. In intervention study reductions in liver fat correlated with restoration of IGFBP2 serum levels to values found in healthy individuals in morbidly obese patients following bariatric surgery. Conclusion: In hepatic metabolism changes of IGFBP2 abundance is connected to lipid metabolism whereas changes in IGFBP2 secretion were directly reflected in the circulation. IGFBP2 serum concentration correlates with the degree of fatty liver, which seems to be related to plasticity of the adipose tissue. These data provide IGFBP2 as a potential non-invasive biomarker for fatty liver disease directly reflecting the degree of impaired liver function with the potential to indicate progressed fatty liver disease.
2020-06-29 | GSE139901 | GEO
Project description:IGFBP2 is one of the putative biomarker of Afatinib response we identified. To dissect the biological processes sustained by IGFBP2 expression, we performed bulk 3’ RNA-seq of MDA-MB-468 cell line over-expressing it
2024-03-25 | GSE228272 | GEO
Project description:Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin ?1 and down- stream invasion pathways, requires ILK to induce cell motility, and activates NF-?B. Most significantly, the IGFBP2/integrin/ILK/NF-?B network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients. We performed cDNA microarray analysis to compare two stably expressing cell lines originating from SNB19; two clones expressing a mutant form of IGFBP2 that cannot bind integrin (RGD ? RGE point mutation; referred to as RGE mutant); and two clones expressing wild-type IGFBP2. SNB19 clones transfected with empty vector were placed in the reference channel in each hybridization.
2012-02-02 | E-GEOD-35467 | biostudies-arrayexpress
Project description:The study was carried out to identify the genes regulated upon IGFBP2 modulation in breast cancer. This will help to understand the molecular targets and biological pathways targeted by IGFBP2 in breast cancer.
2013-09-06 | GSE40682 | GEO