RNAseq analysis of hematopoietic stem cells isolated from control and Regnase1 null mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE125546 | GEO | 2019/01/25
REPOSITORIES: GEO
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Project description:Regnase-2/MCPIP2/ZC3H12B is a protein belonging to the ZC3H12 protein family. There are three other proteins of this family present in humans of which Regnase-1/MCPIP1/ZC3H12A is the founder member as well as the best-described protein. All proteins of this family contain a NYN domain with endoribonuclease activity and a CCCH-type zinc finger responsible for interaction with substrate RNA. Although the NYN domain has a high degree of similarity across all four members the in vitro RNase activity was shown only for two of them, namely Regnase-1 and Regnase-3. Interestingly the ZC3H12 family proteins have unique expression patterns with Regnase-2 being expressed almost solely in the central nervous system. What is more, Regnase-2 is downregulated in human glioblastoma, and its expression is inversely correlated with tumor grade. To decipher the role of Regnase-2 in human glioblastoma we performed RNA sequencing of U-251 MG cells overexpressing Regnase-2 and control, mock-transfected cells.
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Project description:Osteolineage cell-derived extracellular vesicles (EVs) play a regulatory role in hematopoiesis and have been shown to promote the ex vivo expansion of human hematopoietic stem and progenitor cells (HSPCs). Here, we demonstrate that EVs from different human osteolineage sources do not have the same HSPC expansion promoting potential. Comparison of stimulatory and non-stimulatory osteolineage EVs by next-generation sequencing and mass spectrometry analyses revealed distinct microRNA and protein signatures identifying EV-derived candidate regulators of ex vivo HSPC expansion. Accordingly, the treatment of umbilical cord blood-derived CD34+ HSPCs with stimulatory EVs altered HSPC transcriptome, including genes with known roles in cell proliferation. An integrative bioinformatics approach, which connects the HSPC gene expression data with the candidate cargo in stimulatory EVs, delineated the potentially targeted biological functions and pathways during hematopoietic cell expansion and development. In conclusion, our study gives novel insights into the complex biological role of EVs in osteolineage cell-HSPC crosstalk and promotes the utility of EVs and their cargo as therapeutic agents in regenerative medicine.
2020-02-28 | PXD017172 | Pride
Project description:Hematopoietic cell fate decisions such as self-renewal and differentiation are highly regulated through multiple molecular pathways. One pathway, the ubiquitin proteasome system (UPS), controls protein levels by tagging them with polyubiquitin chains and promoting their degradation through the proteasome. Ubiquitin E3 ligases serve as the substrate-recognition component of the UPS. Through investigating the FBOX family of E3 ligases, we discovered that Fbxo21 was highly expressed in the hematopoietic stem and progenitor cell (HSPC) population, and showed low to no expression in mature myeloid populations. To determine the role of FBXO21 on HSPC maintenance, self-renewal, and differentiation, we generated shRNAs against FBXO21 and a hematopoietic specific Fbxo21 conditional knockout (cKO) mouse model. We found that silencing FBXO21 in HSPCs led to a loss in colony formation and an increase in cell differentiation in vitro. Additionally, stressing the HSPC populations in our Fbxo21 cKO mouse with 5-FU injections resulted in a decrease in survival, despite these populations showing minimal alterations during steady-state hematopoiesis. Although FBXO21 has previously been proposed to regulate cytokine signaling via ASK and p38, our results show that depletion of FBXO21 led to altered ERK signaling in vitro. Together, these findings suggest ubiquitin E3 ligase FBXO21 regulates HSPCs through cytokine mediated pathways.
2022-11-11 | PXD035283 | Pride
Project description:Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. However, how stress hematopoiesis, including bone marrow transplantation, induces metabolic changes in hematopoietic stem/progenitor cells (HSPCs) remains unclear. Here, we report a critical role for the p38MAPK family isoform p38α in initiating HSPC proliferation during stress hematopoiesis in mouse. We found that p38MAPK is immediately phosphorylated in HSPCs after hematological stress. p38α loss resulted in defective recovery from hematological stress and a delay in initiation of HSPC cycling. Bone marrow transplant altered levels of amino acids and purine-related metabolites in a p38α-dependent manner. Mechanistically, p38α signaling increases expression of inosine-5’-monophosphate dehydrogenase 2 in HSPCs after transplantation, an activity correlated with perturbed cell cycle progression in vitro and in vivo. Overall, we propose a novel mechanism governing HSPC cell cycle initiation via metabolic signaling in response to stress.
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Project description:Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are underexplored. Here we report that a novel somite-derived pro-hematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch upregulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide ChIP-seq, RNA-seq, and ATAC-seq indicate that Srebp2 trans-regulates Notch pathway genes required for hematopoiesis. Our studies outline a novel AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
2019-05-23 | GSE122204 | GEO
Project description:U2AF1 is involved in the recognition of the 3’ splice site during pre-mRNA splicing. Mutations in U2AF1 are frequently observed in myelodysplastic syndromes. However, the role of wild-type U2AF1 in normal hematopoiesis has remained elusive. Using a novel conditional U2af1 knockout allele, we have found that deletion of U2af1 results in profound defects in hematopoiesis characterized by pancytopenia, ablation of hematopoietic stem/progenitor cells (HSPC) leading to bone marrow failure and early lethality in mice. U2af1 deletion impairs HSPC function and repopulation capacity. U2af1 deletion also causes increased DNA damage and reduced survival in hematopoietic progenitors. RNA sequencing analysis reveals significant alterations in the expression of genes related to HSC maintenance, cell proliferation and DNA damage response-related pathways in U2af1-deficient HSPC. U2af1 deficiency also induces splicing alterations in genes important for HSPC function. Collectively, these results suggest an important role for U2af1 in the maintenance and function of HSPC in normal hematopoiesis. A better understanding of the normal function of U2AF1 in hematopoiesis is important for development of appropriate therapeutic approaches for U2AF1 mutant induced hematologic malignancies.
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2012-06-17 | E-GEOD-33280 | biostudies-arrayexpress
Project description:Increased expression of Kruppel like factor 7 (KLF7) is an independent predictor of poor outcome in pediatric acute lymphoblastic leukemia. The contribution of KLF7 to hematopoiesis has not been previously described. Herein, we characterized the effect on murine hematopoiesis of the loss of KLF7 and enforced expression of KLF7. Long-term multilineage engraftment of Klf7-/- cells was comparable to control cells, and self-renewal, as assessed by serial transplantation, was not affected. Enforced expression of KLF7 results in a marked suppression of myeloid progenitor cell growth and a loss of short- and long-term repopulating activity. Interestingly, enforced expression of KLF7, while resulting in multi-lineage growth suppression that extended to hematopoietic stem cells and common lymphoid progenitors, spared T cells and enhanced the survival of early thymocytes. RNA expression profiling of KLF7-overexpressing hematopoietic progenitors identified several potential target genes mediating these effects. Notably, the known KLF7 target Cdkn1a (p21Cip1/Waf1) was not induced by KLF7, and loss of CDKN1A does not rescue the repopulating defect. These results suggest that KLF7 is not required for normal hematopoietic stem and progenitor (HSPC) function, but increased expression, as seen in a subset of lymphoid leukemia, inhibits myeloid cell proliferation and promotes early thymocyte survival. KLF7 KO vs WT HSPC expression array: KLS (lineage- c-Kit+ Sca-1+) cells were sorted from the bone marrow of Klf7-/- chimeras at 12 weeks post-transplant. Fetal liver cells were used to establish chimeric mice (C57Bl/6 background) containing a mixture of Klf7+/+ and Klf7-/- bone marrow cells.
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Project description:we investigate the role of YTHDC1 in normal hematopoiesis and adult hematopoietic stem/progenitor cell (HSPC) maintenance in vivo. Utilizing conditional Ythdc1 knockout mice ,we show that YTHDC1 is required for hematopoietic stem cell (HSC) maintenance as well as self-renewal of HSC. Transcriptome analysis identified many differentially expressed genes (DEGs) between WT and YTHDC1-KO LT-HSCs.
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Project description:Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Krüppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development through soluble microenvironmental proteins. Mice with inactivated Zfp521 genes (Zfp521-/-) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes BM microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis and towards granulopoiesis. These results advance our understanding of ZFP521’s role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.
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