Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA401869 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells
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Project description:RNA-dependent chromatin targeting of TET2 for endogenous retrovirus control in pluripotent stem cells [RNA-Seq]
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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 | GSE269958 | 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 | GSE269961 | 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 | GSE269960 | 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
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:Pluripotent stem cells are defined by their self-renewal capacity, which is the ability of the stem cells to proliferate indefinitely while maintaining the pluripotent identity essential for their ability to differentiate into any somatic cell lineage. However, understanding the mechanisms that control stem cell fitness versus the pluripotent cell identity is challenging. To investigate the interplay between these two aspects of pluripotency, we performed four parallel genome-scale CRISPR-Cas9 loss-of-function screens interrogating stem cell fitness in hPSC self-renewal conditions, and the dissolution of the primed pluripotency identity during early differentiation. Comparative analyses led to the discovery of genes with distinct roles in pluripotency regulation, including mitochondrial and metabolism regulators crucial for stem cell fitness, and chromatin regulators that control pluripotent identity during early differentiation. We further discovered a core set of factors that control both stem cell fitness and pluripotent identity, including a network of chromatin factors that safeguard pluripotency. Our unbiased and systematic screening and comparative analyses disentangle two interconnected aspects of pluripotency, provide rich datasets for exploring pluripotent cell identity versus cell fitness, and offer a valuable model for categorizing gene function in broad biological contexts.
2024-09-05 | PXD055592 | Pride
Project description:Improved understanding of mechanisms regulating myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cell (HSPC) growth and self-renewal is critical for developing MDS therapy. We revealed a novel regulatory axis that SIRT1-deficiency induced TET2 hyperacetylation promotes MDS HSPC functions, and provide an approach to target MDS HSPCs by activating SIRT1 deacetylase. Four Groups: Group1: MDS-L cells transduced with lentiviral vector targeting non-silence squence (control shRNA for SIRT1); Group2: MDS-L cells transduced with lentiviral vector containing interference squence targeting SIRT1 (SIRT shRNA); Group 3: MDS-L cells transduced with lentiviral vector targeting non-silence squence (control shRNA for TET2); Group 4: MDS-L cells transduced with lentiviral vector containing interference squence targeting TET2 (TET2 shRNA).
2018-08-13 | GSE117272 | GEO