Erythropoietin Exposure Impairs B Cell Development and Promotes Myeloid-Imprinted Biphenotypic Progenitors
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PROVIDER: PRJNA1222388 | ENA |
REPOSITORIES: ENA
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Project description:Erythropoietin (EPO) is the major regulator of erythropoiesis, with levels increasing in response to anemia or hypoxia. Recombinant human EPO (rhEPO) is commonly used to treat anemia in patients with chronic kidney disease or cancer. Beyond its role in erythropoiesis, EPO exerts immunomodulatory effects. Emerging evidence suggests that EPO modulates other hematopoietic lineages, such as megakaryocytes while negatively impacting B-cell development. However, its influence on lympho-hematopoiesis remains insufficiently explored. We investigated the effects of EPO on B lymphopoiesis in the context of hyper-EPOemia-induced stress hematopoiesis. Using an EPO supplementation model in C57BL/6 mice, we demonstrate that EPO impairs B lymphopoiesis during Pre-Pro-B to Pro-B transition, by downregulating essential receptor like IL-7 receptor. Conversely, EPO promotes early B-cell development at the common lymphoid progenitor (CLP) and Pre-Pro-B stages. Remarkably, EPO induces the emergence of atypical B-cell precursors with a myeloid imprint, including CSF1R/CD115-expressing CLPs and CD11b and CD16/32-expressing Pre-Pro-B cells. Gene expression profiling revealed that EPO reprograms early B-cell precursors, upregulating a myeloid transcriptional signature while downregulating B-lymphoid identity genes as for instance genes targeted by key transcription factors IRF4, FOXO1, ERG and IRF8. Additionally, EPO exposure impairs hematopoietic stem and progenitor cell proliferation, induces oxidative stress and disrupts iron homeostasis. We additionally observed lymphoid over myeloid progenitor imbalance in the bone marrow and increased extramedullary hematopoiesis in the spleen. In conclusion, hyper-EPOemia reprograms B lymphopoiesis and promotes the emergence of mixed-lineage myeloid-like B cells. Future studies will explore EPO’s effects on lymphoid progenitor fate under hypoxic and infectious conditions.
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Project description:Chromosomal rearrangements are a hallmark of acute lymphoblastic leukemia (ALL) and are important ALL initiating events. We describe four different rearrangements of the erythropoietin receptor gene EPOR in Philadelphia chromosome-like (Ph-like) ALL. All of these rearrangements result in truncation of the cytoplasmic tail of EPOR at residues similar to those mutated in primary familial congenital polycythemia, with preservation of the proximal tyrosine essential for receptor activation and loss of distal regulatory residues. This resulted in deregulated EPOR expression, hypersensitivity to erythropoietin stimulation, and heightened JAK-STAT activation. Expression of truncated EPOR in mouse B cell progenitors induced ALL in vivo. Human leukemic cells with EPOR rearrangements were sensitive to JAK-STAT inhibition, suggesting a therapeutic option in high-risk ALL.
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Project description:DNA methylation mediated epigenetic regulation plays a critical role in regulating cardiomyocytes (CM) differentiation. Tet protein mediated DNA methylation oxidation have been reported to play an important role in regulating embryonic stem cell (ESC) differentiation toward different lineages. In our study, we utilized CRISPR/Cas9 based genome editing method to generated Tet single, double and triple deficient mouse ESC (mESC) expressing emGFP under NKX2.5 promoter and differentiated these cells toward CM progenitors. By modulating emGFP population as cardiac progenitor cells, we found that deletion of Tet1 and Tet2 significantly impairs mESC differentiation toward CM progenitors. Further single-cell RNA-seq analysis in differentiated control and Tet-triple knockout (TKO) mESC reveals that Tet deletion resulted in accumulation of mesoderm progenitors and impairs CM differentiation. Overexpression the catalytic domain of Tet1 could rescue the development defects in Tet-TKO mESC and restore NKX2.5 gene expression. In addition, loci-specific dCas9-Tet1CD mediated epigenome editing at Hand1 loci confirmed its directly transcriptional regulation during CM differentiation. Overall, out studies suggested that Tet protein mediated epigenomic remodeling is a genome-wide event and is essential to maintain proper transcription network during mESC differentiation toward CM progenitors.
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Project description:Parental imprinting results in a monoallelic parent-of-origin dependent gene expression. However, many imprinted genes identified by differential methylation do not exhibit complete monoallelic expression. Previous studies demonstrated a complex tissue-dependent expression patterns for some imprinted genes. Still, the complete magnitude of this phenomenon remains largely unknown. Differentiating human parthenogenetic induced pluripotent stem cells into different cell types and combining DNA methylation with novel 5' RNA sequencing methodology, enabled us to identify tissue- and isoform-dependent imprinted genes in a genome wide manner. We show that nearly half of all imprinted genes expresses both biallelic and monoallelic isoforms, that are controlled by tissue specific alternative promoters. This study provides the first global analysis of tissue-specific imprinting in humans, and implies that alternative promoters are central in the regulation of imprinted genes. Gene expression analysis was performed on a total of 6 human cell lines, including 4 iPSCs differentiated to neural progenitors and sorted using NCAM1 (2 control and 2 Parthenogenetic), and 2 iPSCs differentiated to endodermal progenitors (1 Control and 1 Parthenogenetic)
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Project description:The regulatory system of erythropoiesis through erythropoietin (EPO) and its receptor (EPOR) is essential for vertebrates' life. In humans, EPO affects the erythroid progenitors and stimulates proliferation and differentiation. The EPO-EPOR axis is mainly mediated by the JAK2-STAT5 pathway. After terminal maturation, erythrocytes lost EPOR expression; however, erythrocytes of amphibian Xenopus tropicalis maintain EPOR expression even after their terminal maturation. Because erythrocytes of vertebrates except for adult mammals are nucleated, we hypothesized that EPO can alter its transcriptional state. To explore the effects of EPO on Xenopus mature erythrocytes, we performed RNA-Seq analysis on EPO-stimulated Xenopus peripheral blood cells. The EPO-stimulated group showed increased expression of direct target genes of STAT such as cish, socs3, and socs1 indicating a functional signal transduction system. Furthermore, we observed several EPO-responsive genes that were not reported in mammalian erythroid progenitors. These findings suggest the functional difference between enucleated erythrocytes in adult mammals and nucleated erythrocytes in fetal mammals and non-mammalian vertebrates.
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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.
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