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:Differentiation therapy has proven to be curative for the rare acute myeloid leukemia (AML) subtype, the acute promyelocytic leukemia (APL). However, whether differentiation induction is a generalizable therapeutic approach for AML and beyond remains incompletely understood. In this study, we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the Wnt pathway GSK3β kinase (GSK3βi) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumor burden in a xenograft mouse model. Mechanistically, this combination promotes differentiation by activating genes in the type I interferon pathway (IFN-I) via inducing expression of IRF7 (LSD1i) and b-catenin (GSK3i) and their selective co-occupancy at targets such as STAT1, which is necessary for combination-indued differentiation. Combination treatment also suppresses the canonical, pro-oncogenic Wnt pathway and cell cycle genes. Importantly, analysis of AML patient datasets suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, our findings suggest that this combination strategy re-wires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and Wnt-driven cancers beyond AML.
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Project description:An epigenetic-signaling pathway interplay re-wires transcriptional program to induce therapeutic differentiation of AML
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Project description:An epigenetic-signaling pathway interplay re-wires transcriptional program to induce therapeutic differentiation of AML
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Project description:While most current therapies for acute myeloid leukemia (AML) suffer from limited efficacy and substantial toxicity, differentiation therapy has proven to be curative for the rare AML subtype, acute promyelocytic leukemia (APL). However, whether differentiation induction is a generalizable therapeutic approach for AML and beyond remains incompletely understood. In this study, we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the Wnt pathway GSK3β kinase (GSK3βi) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumor burden in a xenograft mouse model. Mechanistically, this combination treatment induces selective co-occupancy of IRF7 and b-catenin at promoters of the type I interferon signaling pathway component genes such as STAT1 essential for AML differentiation, and key downstream target genes, and consequently their expression. Combination treatment also suppresses the canonical, pro-oncogenic Wnt pathway and activates a pro-differentiation transcription program. Importantly, analysis of AML patient datasets suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, our findings suggest that this combination strategy re-wires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and Wnt-driven cancers beyond AML.
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Project description:While most current therapies for acute myeloid leukemia (AML) suffer from limited efficacy and substantial toxicity, differentiation therapy has proven to be curative for the rare AML subtype, acute promyelocytic leukemia (APL). However, whether differentiation induction is a generalizable therapeutic approach for AML and beyond remains incompletely understood. In this study, we demonstrate that simultaneous inhibition of the histone demethylase LSD1 (LSD1i) and the Wnt pathway GSK3β kinase (GSK3βi) robustly promotes therapeutic differentiation of established AML cell lines and primary human AML cells, as well as reducing tumor burden in a xenograft mouse model. Mechanistically, this combination treatment induces selective co-occupancy of IRF7 and b-catenin at promoters of the type I interferon signaling pathway component genes such as STAT1 essential for AML differentiation, and key downstream target genes, and consequently their expression. Combination treatment also suppresses the canonical, pro-oncogenic Wnt pathway and activates a pro-differentiation transcription program. Importantly, analysis of AML patient datasets suggests a correlation between the combination-induced transcription signature and better prognosis, highlighting clinical potential of this strategy. Collectively, our findings suggest that this combination strategy re-wires transcriptional programs to suppress stemness and to promote differentiation, which may have important therapeutic implications for AML and Wnt-driven cancers beyond AML.
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