Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA137933 | ENA |
REPOSITORIES: ENA
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Project description:Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation. These studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentitiation Gene expression profiles from WT and Tet2-/- sorted LSK and myeloid progenitors (CMP and GMP) were compared using genome wide mRNA expression profiling by Affymetrix genechip arrays (Mouse 430 2.0) and key targets were validated by chromatin immunoprecipitation experiments.
2011-07-01 | E-GEOD-27816 | biostudies-arrayexpress
Project description:Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation. These studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentitiation
2011-07-01 | GSE27816 | GEO
Project description:Recent studies have uncovered that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 in various myeloid malignancies and aberrant hematopoietic stem cell (HSC) self-renewal/differentiation in mice with hematopoietic tissue specific loss of Tet2 have been reported, indicating that TET2 is a master regulator of normal and malignant hematopoiesis. Despite a functional link between AID and TET in epigenetic gene regulation, the role of AID loss in normal hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and contraction in erythroid progenitors resulting in pathologic anemia possibly due to dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage specific transcription factors. Consistent with data in the murine context, silencing of AID skews differentiation towards myelomonocytic lineage in human BM cells. However, in contrast to Tet2, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD in myeloid leukemogenesis. Genome-wide transcription and differential methylation analysis uncover critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, and that their role is non-redundant in regulating HSC self-renewal and in myeloid transformation.
2017-10-01 | GSE88841 | GEO
Project description:Recent studies have uncovered that activation-induced cytidine deaminase (AID) and ten-eleven-translocation (TET) family members regulate active DNA demethylation. Genetic alterations of TET2 in various myeloid malignancies and aberrant hematopoietic stem cell (HSC) self-renewal/differentiation in mice with hematopoietic tissue specific loss of Tet2 have been reported, indicating that TET2 is a master regulator of normal and malignant hematopoiesis. Despite a functional link between AID and TET in epigenetic gene regulation, the role of AID loss in normal hematopoiesis and myeloid transformation remains to be investigated. Here, we show that Aid loss in mice leads to expansion of myeloid cells and contraction in erythroid progenitors resulting in pathologic anemia possibly due to dysregulated expression of Cebpa and Gata1, myeloid/erythroid lineage specific transcription factors. Consistent with data in the murine context, silencing of AID skews differentiation towards myelomonocytic lineage in human BM cells. However, in contrast to Tet2, Aid loss does not contribute to enhanced HSC self-renewal or cooperate with Flt3-ITD in myeloid leukemogenesis. Genome-wide transcription and differential methylation analysis uncover critical role of Aid as a key epigenetic regulator. These results indicate that AID and TET2 share common effects on myeloid and erythroid lineage differentiation, and that their role is non-redundant in regulating HSC self-renewal and in myeloid transformation.
2017-10-01 | GSE88842 | GEO
Project description:Increasing evidence links metabolic activity and cell growth to decline in hematopoietic stem cell (HSC) function during aging. The Lin28b/Hmga2 pathway controls tissue development and in the hematopoietic system the postnatal downregulation of this pathway causes a decrease in self renewal of adult HSCs compared to fetal HSCs. Igf2bp2 is an RNA binding protein and a mediator of the Lin28b/Hmga2 pathway, which regulates metabolism and growth signaling by influencing RNA stability and translation of its target genes. It is currently unknown whether Lin28/Hmga2/Igf2bp2 signaling impacts on aging-associated impairments in HSC function and hematopoiesis. Here, we analyzed homozygous Igf2bp2 germline knockout mice and wildtype control animals to address this question. The study shows that Igf2bp2 deletion rescues aging phenotypes of the hematopoietic system, such as the expansion of HSC numbers in bone marrow and the biased increase of myeloid cells in peripheral blood. This rescue of hematopoietic aging coincides with reduced mitochondrial metabolism and glycolysis in Igf2bp2-/- HSCs compared to Igf2bp2+/+ HSCs. Conversely, Igf2bp2 overexpression activates protein synthesis pathways in HSCs and leads to a rapid loss of self renewal by enhancing myeloid skewed differentiation in an mTOR/PI3K-dependent manner. Together, these results show that Igf2bp2 regulates energy metabolism and growth signaling in HSCs and that the activity of this pathways influences self renewal, differentiation, and aging of HSCs.
2024-05-21 | PXD018535 | Pride
Project description:Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.
2005-08-16 | E-SMDB-3450 | biostudies-arrayexpress
Project description:Hematopoitic stem cells from Utx/p53 DKO mice showed increased self-renewal potential and predisposition of differentiation to myeloid lineage compared with those from p53 KO mice. To figure out what mechanism leads to the increased self-renewal, we compared the transcriptional profiles using RNA-sequencing of FACS sorted LSK (Lin-Ckit+Sca1+) cells, which contains the hematopoietic stem cells.
2018-10-08 | GSE97737 | GEO
Project description:Mutation of Ten-eleven translocation enzyme 2 (TET2) drives myeloid malignancy initiation and progression. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant hematopoietic stem cell self-renewal. However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukemic cells and hematopoietic progenitor and stem cells is inconsistent with the designated role of DNA 5mC oxidation of TET2. We show here that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C) can be recognized by the methyl-CpG-binding domain protein MBD6, which guides deubiquitination of nearby histone H2AK119ub to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. Thereby, TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription in stem cells. TET2 mutant human leukemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocks proliferation of TET2 mutant leukemic cells and fully reverses the hematopoiesis defects caused by Tet2 loss, both in vitro and in vivo. Altogether, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.
2024-07-25 | GSE271464 | GEO
Project description:Mutation of Ten-eleven translocation enzyme 2 (TET2) drives myeloid malignancy initiation and progression. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant hematopoietic stem cell self-renewal. However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukemic cells and hematopoietic progenitor and stem cells is inconsistent with the designated role of DNA 5mC oxidation of TET2. We show here that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C) can be recognized by the methyl-CpG-binding domain protein MBD6, which guides deubiquitination of nearby histone H2AK119ub to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. Thereby, TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription in stem cells. TET2 mutant human leukemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocks proliferation of TET2 mutant leukemic cells and fully reverses the hematopoiesis defects caused by Tet2 loss, both in vitro and in vivo. Altogether, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.
2024-07-25 | GSE271463 | GEO
Project description:Mutation of Ten-eleven translocation enzyme 2 (TET2) drives myeloid malignancy initiation and progression. TET2 deficiency is known to cause a globally opened chromatin state and activation of genes contributing to aberrant hematopoietic stem cell self-renewal. However, the open chromatin observed in TET2-deficient mouse embryonic stem cells, leukemic cells and hematopoietic progenitor and stem cells is inconsistent with the designated role of DNA 5mC oxidation of TET2. We show here that chromatin-associated retrotransposon RNA 5-methylcytosine (m5C) can be recognized by the methyl-CpG-binding domain protein MBD6, which guides deubiquitination of nearby histone H2AK119ub to promote an open chromatin state. TET2 oxidizes m5C and antagonizes this MBD6-dependent H2AK119ub deubiquitination. Thereby, TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription in stem cells. TET2 mutant human leukemia becomes dependent on this gene activation pathway, with MBD6 depletion selectively blocks proliferation of TET2 mutant leukemic cells and fully reverses the hematopoiesis defects caused by Tet2 loss, both in vitro and in vivo. Altogether, our findings reveal a chromatin regulation pathway by TET2 through retrotransposon RNA m5C oxidation and identify the downstream MBD6 protein as a feasible target for developing therapies specific against TET2 mutant malignancies.
2024-07-25 | GSE269959 | GEO