Erythropoietin re-wires cognition-associated transcriptional networks
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ABSTRACT:
PROVIDER: PRJNA910128 | ENA |
REPOSITORIES: ENA
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Project description:Recombinant human erythropoietin (rhEPO) has potent procognitive effects, likely hematopoiesis-independent, but underlying mechanisms and physiological role of brain-expressed EPO remained obscure. Here, we provide transcriptional hippocampal profiling of male mice treated with rhEPO. Based on ~108,000 single nuclei, we unmask multiple pyramidal lineages with their comprehensive molecular signatures. By temporal profiling and gene regulatory analysis, we build developmental trajectory of CA1 pyramidal neurons derived from multiple predecessor lineages and elucidate gene regulatory networks underlying their fate determination. With EPO as ꞌtoolꞌ, we discover populations of newly differentiating pyramidal neurons, overpopulating to ~200% upon rhEPO with upregulation of genes crucial for neurodifferentiation, dendrite growth, synaptogenesis, memory formation, and cognition. Using a Cre-based approach to visually distinguish pre-existing from newly formed pyramidal neurons for patch-clamp recordings, we learn that rhEPO treatment differentially affects excitatory and inhibitory inputs. Our findings provide mechanistic insight into how EPO modulates neuronal functions and networks.
2023-06-16 | GSE220522 | GEO
Project description:Recombinant human erythropoietin (rhEPO) has potent procognitive effects, likely hematopoiesis-independent, but underlying mechanisms and physiological role of brain-expressed EPO remained obscure. Here, we provide transcriptional hippocampal profiling of male mice treated with rhEPO. Based on ~108,000 single nuclei, we unmask multiple pyramidal lineages with their comprehensive molecular signatures. By temporal profiling and gene regulatory analysis, we build developmental trajectory of CA1 pyramidal neurons derived from multiple predecessor lineages and elucidate gene regulatory networks underlying their fate determination. With EPO as 'tool', we discover populations of newly differentiating pyramidal neurons, overpopulating to ~200% upon rhEPO with upregulation of genes crucial for neurodifferentiation, dendrite growth, synaptogenesis, memory formation, and cognition. Using a Cre-based approach to visually distinguish pre-existing from newly formed pyramidal neurons for patch-clamp recordings, we learn that rhEPO treatment differentially affects excitatory and inhibitory inputs. Our findings provide mechanistic insight into how EPO modulates neuronal functions and networks.
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Project description:Erythropoietin Signaling Regulates Key Epigenetic and Transcription Networks in Fetal Neural Progenitor Cells
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Project description:We have established a novel mouse model for postnatal erythropoietin (Epo)-deficiency anaemia, designated ISAM (inherited super anemic mouse) using a transgenic complementation rescue technique. To identify responsible signals for myofibroblastic transformation of Renal Erythropoietin-producing cells (REPs), we examined the mRNA expression profile of whole ISAM kidneys that underwent reversible UUO model.
2013-03-20 | GSE45304 | GEO
Project description:Crosstalk and complexity within signaling pathways has limited our ability to devise rational strategies for using network biology to treat human disease. This is particularly problematic in cancer where oncogenes that drive or maintain the tumorigenic state alter the normal flow of molecular information within signaling networks that control growth, survival and death. Understanding the architecture of oncogenic signaling pathways, and how these networks are re-wired by ligands or drugs, could provide opportunities for the specific targeting of oncogene-driven tumors. Here we use a systems biology-based approach to explore synergistic therapeutic strategies to optimize the killing of triple negative breast cancer cells, an incompletely understood tumor type with a poor treatment outcome. Using targeted inhibition of oncogenic signaling pathways combined with DNA damaging chemotherapy, we report the surprising finding that time-staggered EGFR inhibition, but not simultaneous co-administration, can dramatically sensitize the apoptotic response of a subset of triple-negative cells to conventional DNA damaging agents. A systematic analysis of the order and timing of inhibitor/genotoxin presentation—using a combination of high-density time-dependent activity measurements of signaling networks, gene expression profiles, cell phenotypic responses, and mathematical modeling—revealed an approach for altering the intrinsic oncogenic state of the cell through dynamic re-wiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death, through re-activation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state. Three or 4 replicates of 3 different cell lines at time points 0minutes, 30minutes, 6 hours and 1 day after EGFR inhibition with erlotinib
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Project description:The transcriptional and regulatory identity of erythropoietin producing cells
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Project description:Time-resolved CFU-E proteome was analyzed by time collapsed super-SILAC with erythropoietin-stimulated BaF3-mEpoR proteome as internal heavy standard.
2022-09-28 | PXD004539 | Pride
Project description:We have established a novel mouse model for postnatal erythropoietin (Epo)-deficiency anaemia, designated ISAM (inherited super anemic mouse) using a transgenic complementation rescue technique. To identify responsible signals for myofibroblastic transformation of Renal Erythropoietin-producing cells (REPs), we examined the mRNA expression profile of whole ISAM kidneys that underwent reversible UUO model. Unilateral ureteral obstruction (UUO)-induced gene expression changes were analyzed. Three UUO-treated samples (Clip), three reversed UUO kidneys (ClipR-14), and two sham-treated and one untreated samples were compared.
2013-03-20 | E-GEOD-45304 | biostudies-arrayexpress
Project description:Crosstalk and complexity within signaling pathways has limited our ability to devise rational strategies for using network biology to treat human disease. This is particularly problematic in cancer where oncogenes that drive or maintain the tumorigenic state alter the normal flow of molecular information within signaling networks that control growth, survival and death. Understanding the architecture of oncogenic signaling pathways, and how these networks are re-wired by ligands or drugs, could provide opportunities for the specific targeting of oncogene-driven tumors. Here we use a systems biology-based approach to explore synergistic therapeutic strategies to optimize the killing of triple negative breast cancer cells, an incompletely understood tumor type with a poor treatment outcome. Using targeted inhibition of oncogenic signaling pathways combined with DNA damaging chemotherapy, we report the surprising finding that time-staggered EGFR inhibition, but not simultaneous co-administration, can dramatically sensitize the apoptotic response of a subset of triple-negative cells to conventional DNA damaging agents. A systematic analysis of the order and timing of inhibitor/genotoxin presentation—using a combination of high-density time-dependent activity measurements of signaling networks, gene expression profiles, cell phenotypic responses, and mathematical modeling—revealed an approach for altering the intrinsic oncogenic state of the cell through dynamic re-wiring of oncogenic signaling pathways. This process converts these cells to a less tumorigenic state that is more susceptible to DNA damage-induced cell death, through re-activation of an extrinsic apoptotic pathway whose function is suppressed in the oncogene-addicted state.
2012-05-15 | GSE30516 | GEO
Project description:In this work, we use RNAi and subsequent RNA isolation and Affymetrix Expression array analysis to map the genome-wide transcriptional targets of 107 of the strongest cell cycle regulators. Drosophila S2 cells were used with RNAi target gene knockdown compared to control (GFP dsRNA). RMA normalized data re-annotated using a custom CDF is available on the FTP site for this experiment. E-MTAB-1648, E-MTAB-1364 and E-MTAB-453 are all data from: Bonke M, et al. (2013) Transcriptional networks controlling the cell cycle. G3 (Bethesda) 3, 75-90, PMID: 23316440.
2012-06-30 | E-MTAB-453 | biostudies-arrayexpress