Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA125313 | ENA |
REPOSITORIES: ENA
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Project description:Hematopoietic stem cells (HSCs) and lymphoid-primed multi-potential progenitors (LMPPs) are able to initiate both lymphoid and myeloid differentiation. We show here that the transcriptional repressor Gfi1 (growth factor independence 1) implements a specific gene expression program in HSCs and LMPPs that is critical for their survival and lymphoid differentiation potential. We present evidence that Gfi1 is required to maintain expression of genes involved in lymphoid development such as Flt-3, IL7R, Ebf1, Rag1, CCR9 and Notch1 and controls myeloid lineage commitment by regulating expression of genes such as Hoxa9 or M-CSFR. Gfi1 also inhibits apoptosis in HSCs by repressing pro-apoptotic genes such as Bax or Bak. As a consequence, Gfi1-/- mice show defects in self renewal, survival and both myeloid and lymphoid development of HSCs and LMPPs. Co-expression of a Bcl-2 transgene can partially restore the function of HSCs in Gfi1-/- mice, but not the defects in early lymphoid development. Of interest, Gfi1-/- x Bcl-2 transgenic mice show an accelerated expansion of myeloid cells and succumb to a fatal myeloproliferative disease resembling chronic myelomonocytic leukemia (CMML). Our data show that Gfi1 protects HSCs against apoptosis, ensures the proper development of LMPPs and plays a role in the development of myeloid leukemia. We used microarrays to detail the global gene expression changes following knockout of Gfi1 in mouse LSK cells We compared LSK cells isolated from Gfi1 knockout mice with wildtype cells to determine global gene expression changes by microarray analysis
2011-02-02 | E-GEOD-20282 | biostudies-arrayexpress
Project description:Hematopoietic stem cells (HSCs) and lymphoid-primed multi-potential progenitors (LMPPs) are able to initiate both lymphoid and myeloid differentiation. We show here that the transcriptional repressor Gfi1 (growth factor independence 1) implements a specific gene expression program in HSCs and LMPPs that is critical for their survival and lymphoid differentiation potential. We present evidence that Gfi1 is required to maintain expression of genes involved in lymphoid development such as Flt-3, IL7R, Ebf1, Rag1, CCR9 and Notch1 and controls myeloid lineage commitment by regulating expression of genes such as Hoxa9 or M-CSFR. Gfi1 also inhibits apoptosis in HSCs by repressing pro-apoptotic genes such as Bax or Bak. As a consequence, Gfi1-/- mice show defects in self renewal, survival and both myeloid and lymphoid development of HSCs and LMPPs. Co-expression of a Bcl-2 transgene can partially restore the function of HSCs in Gfi1-/- mice, but not the defects in early lymphoid development. Of interest, Gfi1-/- x Bcl-2 transgenic mice show an accelerated expansion of myeloid cells and succumb to a fatal myeloproliferative disease resembling chronic myelomonocytic leukemia (CMML). Our data show that Gfi1 protects HSCs against apoptosis, ensures the proper development of LMPPs and plays a role in the development of myeloid leukemia. We used microarrays to detail the global gene expression changes following knockout of Gfi1 in mouse LSK cells
2011-02-02 | GSE20282 | GEO
Project description:Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a common integration site in Moloney-murine-leukemia-virus-induced T-cell leukemia. Gfi1-/- mice display increased apoptosis of developing thymocytes and T lymphopenia; however, there are contradictory reports of the absolute number of Gfi1-/- early T lineage progenitors. We used floxed alleles of Gfi1 crossed to various T-cell-specific Cre transgenes to map the requirements for Gfi1 during lymphoid priming and development. We show that Gfi1 is necessary for the proper formation and function of both lymphoid-primed multipotent progenitors and early T lineage progenitors. These defects correlate with a global inability of Gfi1-/- progenitors to enforce the activation of lymphoid genes including IL7R, Rag1, Flt3 and Notch1. Forced expression of intracellular Notch1 fails to rescue the Gfi1-/- defective lymphoid gene signature or Gfi1-/- T cell development. Instead, activation of Notch1 in Gfi1-/- cells results in a potent synthetic lethal phenotype that is most dramatic in immature thymocytes, but absent in mature peripheral T cells where developmental transcriptional programs are silent. Moreover, we find that the requirement for Gfi1-transcriptional integration of Notch-driven lymphoid transcriptional programs is cell autonomous. Our data indicate that Gfi1 is required at multiple independent stages of lymphoid development. In hematopoietic progenitors Gfi1 is necessary to integrate Notch1 signaling, mediate lymphoid priming, the formation of early T lineage progenitors and subsequent T lineage commitment. Lineage negative cells were purified by magnetic beads from RosaCreERT2 Gfi1 ex4-5 floxed mice and an activated Notch1 signal was introduced using a GFP+ retroviral vector. GFP+ progenitors were FACS-sorted and cultured in semi-solid media for one week to allow sufficient time to to instruct lymphoid differentiation, then replated in 1uM 4-OHT or EtOH control. After an additional 7 days, CFU were disrupted and RNA was isolated for global gene expression using microarrays.
2014-10-01 | E-GEOD-41162 | biostudies-arrayexpress
Project description:Growth factor independence genes (Gfi1 and Gfi1b) repress recombination activating genes (Rag) transcription in developing B lymphocytes. Because all blood lineages originate from hematopoietic stem cells (HSCs) and different lineage progenitors have been shown to share transcription factor networks prior to cell fate commitment, we hypothesized that GFI family proteins may also play a role in repressing Rag transcription or a global lymphoid transcriptional program in other blood lineages. We tested the level of Rag transcription in various blood cells when Gfi1 and Gfi1b were deleted, and observed an upregulation of Rag expression in plasmacytoid dendritic cells (pDCs). Using microarray analysis, we observed that Gfi1 and Gfi1b regulate a broad spectrum of cellular processes in pDCs, but not a lymphoid specific transcriptional program. This study establishes a role for Gfi1 and Gfi1b in Rag regulation in a non-B lineage cell type Gfi1f/f; Gfi1bf/f; ERCre bone marrow progenitors were untreated and treated with tamoxifen (4OHT) to delete floxed alleles during pDC differentiation in culture. Cells from three individual mouse constitute triplicates of untreated (-4OHT) and treated (+4OHT) conditions, corresponding to wildtype or knockout genotypes.
2013-04-07 | E-GEOD-45837 | biostudies-arrayexpress
Project description:Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a common integration site in Moloney-murine-leukemia-virus-induced T-cell leukemia. Gfi1-/- mice display increased apoptosis of developing thymocytes and T lymphopenia; however, there are contradictory reports of the absolute number of Gfi1-/- early T lineage progenitors. We used floxed alleles of Gfi1 crossed to various T-cell-specific Cre transgenes to map the requirements for Gfi1 during lymphoid priming and development. We show that Gfi1 is necessary for the proper formation and function of both lymphoid-primed multipotent progenitors and early T lineage progenitors. These defects correlate with a global inability of Gfi1-/- progenitors to enforce the activation of lymphoid genes including IL7R, Rag1, Flt3 and Notch1. Forced expression of intracellular Notch1 fails to rescue the Gfi1-/- defective lymphoid gene signature or Gfi1-/- T cell development. Instead, activation of Notch1 in Gfi1-/- cells results in a potent synthetic lethal phenotype that is most dramatic in immature thymocytes, but absent in mature peripheral T cells where developmental transcriptional programs are silent. Moreover, we find that the requirement for Gfi1-transcriptional integration of Notch-driven lymphoid transcriptional programs is cell autonomous. Our data indicate that Gfi1 is required at multiple independent stages of lymphoid development. In hematopoietic progenitors Gfi1 is necessary to integrate Notch1 signaling, mediate lymphoid priming, the formation of early T lineage progenitors and subsequent T lineage commitment.
2014-10-01 | GSE41162 | GEO
Project description:Growth factor independence genes (Gfi1 and Gfi1b) repress recombination activating genes (Rag) transcription in developing B lymphocytes. Because all blood lineages originate from hematopoietic stem cells (HSCs) and different lineage progenitors have been shown to share transcription factor networks prior to cell fate commitment, we hypothesized that GFI family proteins may also play a role in repressing Rag transcription or a global lymphoid transcriptional program in other blood lineages. We tested the level of Rag transcription in various blood cells when Gfi1 and Gfi1b were deleted, and observed an upregulation of Rag expression in plasmacytoid dendritic cells (pDCs). Using microarray analysis, we observed that Gfi1 and Gfi1b regulate a broad spectrum of cellular processes in pDCs, but not a lymphoid specific transcriptional program. This study establishes a role for Gfi1 and Gfi1b in Rag regulation in a non-B lineage cell type
2013-04-07 | GSE45837 | GEO
Project description:Myelodysplastic syndromes (MDS) are a group of hematologic neoplasms in which the bone marrow fails to produce enough mature blood cells, leading to peripheral blood cytopenias and myeloproliferation1-3. The average survival time following diagnosis of MDS is 2.5 years4, owing to few treatment options5. Roughly 20-30% of MDS patients progress to acute myeloid leukemia6. Risks of allogeneic bone marrow transplants in elderly patients, together with a dearth of effective FDA-approved drugs, make it imperative to revisit the origins of hematopoietic differentiation defects underlying MDS to identify new druggable targets7-9. We recently reported that haploinsufficiency of the atypical kinase Riok2 (Right open reading frame kinase 2)10 in mice leads to anemia and MDS-associated phenotypes11. However, the underlying molecular mechanisms remain largely unexplored. Here we show that RIOK2 is a master transcription factor that not only drives erythroid lineage commitment, but simultaneously suppresses megakaryocytic and myeloid lineages in primary human stem and progenitor cells. Structural modeling, chromatin immunoprecipitation sequencing, ATAC-sequencing and structure-function domain deletion mutants revealed that RIOK2 activates or represses specific genetic programs in hematopoiesis via its previously unappreciated winged helix-turn-helix DNA-binding domain and two transactivation domains. Mechanistically, RIOK2 functions as a master regulator of hematopoietic lineage commitment by controlling the expression of key lineage-specific transcription factors, such as GATA1, GATA2, SPI1, RUNX3 and KLF1. We also show that GATA1 and RIOK2 function in a positive feedback loop to drive erythroid differentiation. These discoveries present novel therapeutic opportunities to correct hematopoietic differentiation defects in MDS, in the anemia of chronic diseases such as renal failure and inflammation, and in other bone marrow failure disorders.
2021-10-16 | MSV000088238 | MassIVE
Project description:Adipocytes arise from commitment and differentiation of adipose precursors in white adipose tissue (WAT). In studying adipogenesis, precursor markers, including Pref-1 and PDGFRα, are used to isolate precursors from stromal vascular fraction of WAT, but the relationship among the markers is not known. Here, we used Pref-1 promoter-rtTA system in mice for labeling Pref-1+ cells and for inducible inactivation of Pref-1 target, Sox9. We show requirement of Sox9 for maintenance of Pref-1+ proliferative, early precursors. Upon Sox9 inactivation, these Pref-1+ cells become PDGFRa+ cells that express early adipogenic markers. Thus, we show for the first time that Pref-1+ cells precede PDGFRa+ cells in the adipogenic pathway and that Sox9 inactivation is required for WAT growth and expansion. Furthermore, we show that, in maintaining early adipose precursors, Sox9 activates Meis1 which prevents adipogenic differentiation. Our study also demonstrates the Pref-1 promoter-rtTA system for inducible gene inactivation in early adipose precursor population. Sox9 ablation increases PDGFRα+ cells, inhibiting cell cycle, muscle and osteoblast/osteoclast differentiation, while inducing genes of hematopoietic cell lineage and inflammatory response.
2018-10-24 | GSE118513 | GEO
Project description:The variation among induced pluripotent stem cells (iPSCs) in their differentiation capacity to specific lineages is frequently attributed to somatic memory. In this study, we compared hematopoietic differentiation capacity of 35 human iPSC lines derived from four different tissues and four embryonic stem cell lines. The analysis revealed that hematopoietic commitment capacity (PSCs to hematopoietic precursors) is correlated with the expression level of the IGF2 gene independent of the iPSC origins. In contrast, maturation capacity (hematopoietic precursors to mature blood) is affected by iPSC origin; blood-derived iPSCs showed the highest capacity. However, some fibroblast-derived iPSCs showed higher capacity than blood-derived clones. Tracking of DNA methylation changes during reprogramming reveals that maturation capacity is highly associated with aberrant DNA methylation acquired during reprogramming, rather than the types of iPSC origins. These data demonstrated that variations in the hematopoietic differentiation capacity of iPSCs are not attributable to somatic memories of their origins. Bisulfite converted genomic DNA lysates from human pluripotent stem cell-derived hematopoietic precursor cells (CD34+CD38-CD43+ lineage marker-) were hybridized to Illumina HumanMethylation450 BeadChip.
2016-06-29 | E-GEOD-60811 | biostudies-arrayexpress
Project description:The variation among induced pluripotent stem cells (iPSCs) in their differentiation capacity to specific lineages is frequently attributed to somatic memory. In this study, we compared hematopoietic differentiation capacity of 35 human iPSC lines derived from four different tissues and four embryonic stem cell lines. The analysis revealed that hematopoietic commitment capacity (PSCs to hematopoietic precursors) is correlated with the expression level of the IGF2 gene independent of the iPSC origins. In contrast, maturation capacity (hematopoietic precursors to mature blood) is affected by iPSC origin; blood-derived iPSCs showed the highest capacity. However, some fibroblast-derived iPSCs showed higher capacity than blood-derived clones. Tracking of DNA methylation changes during reprogramming reveals that maturation capacity is highly associated with aberrant DNA methylation acquired during reprogramming, rather than the types of iPSC origins. These data demonstrated that variations in the hematopoietic differentiation capacity of iPSCs are not attributable to somatic memories of their origins. Bisulfite converted genomic DNA lysates from human pluripotent stem cell-derived hematopoietic precursor cells (CD34+CD38-CD43+ lineage marker-) were hybridized to Illumina HumanMethylation450 BeadChip.
2016-06-29 | E-GEOD-60816 | biostudies-arrayexpress