Arginine methylation of C/EBP⍺ controls the speed of immune cell transdifferentiation (ChIP-Seq)
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE229072 | GEO | 2023/07/05
REPOSITORIES: GEO
Similar Datasets
Project description:C/EBPα is a potent inducer of lymphoid to myeloid cell transdifferentiation. Here we describe that Carm1 methylates arginine 35 in the transactivation domain of C/EBPα, modulating the factor’s activity. Inhibition of methylation or mutation of R35 dramatically enhances the capacity of C/EBPα to induce a B cell-to-macrophage conversion through accelerated chromatin remodeling and subsequent upregulation of myeloid genes and downregulation of B cell genes. This phenomenon is mediated by an increased interaction of unmethylated C/EBPα with the bi-lineage transcription factor PU.1, resulting in the accelerated relocation of PU.1 from B cell to myeloid gene regulatory elements and thus enhancing chromatin remodeling. Our data suggests that C/EBPα effectively converts PU.1 from a B cell to a myeloid regulator through a ‘stealing’ process, and that methylation of C/EBPα by Carm1 modulates this interaction. We propose that individual cells display a pool of methylated and unmethylated C/EBPα, and the proportion of the two molecular forms determines the velocity of cell fate conversion.
2023-07-05 | GSE204742 | GEO
Project description:C/EBPα is a potent inducer of lymphoid to myeloid cell transdifferentiation. Here we describe that Carm1 methylates arginine 35 in the transactivation domain of C/EBPα, modulating the factor’s activity. Inhibition of methylation or mutation of R35 dramatically enhances the capacity of C/EBPα to induce a B cell-to-macrophage conversion through accelerated chromatin remodeling and subsequent upregulation of myeloid genes and downregulation of B cell genes. This phenomenon is mediated by an increased interaction of unmethylated C/EBPα with the bi-lineage transcription factor PU.1, resulting in the accelerated relocation of PU.1 from B cell to myeloid gene regulatory elements and thus enhancing chromatin remodeling. Our data suggests that C/EBPα effectively converts PU.1 from a B cell to a myeloid regulator through a ‘stealing’ process, and that methylation of C/EBPα by Carm1 modulates this interaction. We propose that individual cells display a pool of methylated and unmethylated C/EBPα, and the proportion of the two molecular forms determines the velocity of cell fate conversion.
2023-07-05 | GSE204745 | GEO
Project description:Oncogenic mutations confer aberrant replicative capacity to cells with little or no replicative capacity, generating cancer stem cells that perpetuate the tumor through extensive self-replication and differentiation blockade. However, whether oncogenes disrupt the cellular identity of cancer stem cell by altering the developmental potential is unknown. Fate conversion has been demonstrated by ectopic expression of master transcriptional regulators, such as PU.1 and C/EBPα that confers myeloid cell fate to other cell types, and PRDM16 that confers brown adipose fate to white adipocytes or myoblasts. Here we show that a transcriptional regulator overexpressed in human myeloid malignancies, PRDM16s, causes oncogenic fate conversion, by transforming cells fated to form platelets and erythrocytes into myeloid leukemia-initiating cells (LICs). Prdm16s expression in murine hematopoietic progenitor cells caused a myelodysplastic syndrome (MDS)-like disease that progressed to acute myelogenous leukemia (AML). The myeloid diseases caused by Prdm16s exhibited expansion of megakaryocyte-erythroid progenitors (MEPs) but not granulocyte-macrophage progenitors. MEPs from Prdm16s-induced leukemia possessed LIC potential, and expression of Prdm16s in normal MEPs was sufficient to convert them to myeloid LICs and blocked megakaryocytic/erythroid potential. Prdm16s induced the expression of myeloid master regulators, including PU.1 and C/EBPα, by interacting with their super enhancers. Ablation of myeloid master regulators attenuated the myeloid potential and reinstalled the megakaryocytic/erythroid potential of leukemic-MEPs in mouse models and in human AML with PRDM16 rearrangement. Our study demonstrates that oncogenic PRDM16 expression converts the fate of MEPs to a malignant myeloid fate by activating myeloid master transcription factors.
2019-03-01 | GSE119300 | GEO
Project description:Oncogenic mutations confer aberrant replicative capacity to cells with little or no replicative capacity, generating cancer stem cells that perpetuate the tumor through extensive self-replication and differentiation blockade. However, whether oncogenes disrupt the cellular identity of cancer stem cell by altering the developmental potential is unknown. Fate conversion has been demonstrated by ectopic expression of master transcriptional regulators, such as PU.1 and C/EBPα that confers myeloid cell fate to other cell types, and PRDM16 that confers brown adipose fate to white adipocytes or myoblasts. Here we show that a transcriptional regulator overexpressed in human myeloid malignancies, PRDM16s, causes oncogenic fate conversion, by transforming cells fated to form platelets and erythrocytes into myeloid leukemia-initiating cells (LICs). Prdm16s expression in murine hematopoietic progenitor cells caused a myelodysplastic syndrome (MDS)-like disease that progressed to acute myelogenous leukemia (AML). The myeloid diseases caused by Prdm16s exhibited expansion of megakaryocyte-erythroid progenitors (MEPs) but not granulocyte-macrophage progenitors. MEPs from Prdm16s-induced leukemia possessed LIC potential, and expression of Prdm16s in normal MEPs was sufficient to convert them to myeloid LICs and blocked megakaryocytic/erythroid potential. Prdm16s induced the expression of myeloid master regulators, including PU.1 and C/EBPα, by interacting with their super enhancers. Ablation of myeloid master regulators attenuated the myeloid potential and reinstalled the megakaryocytic/erythroid potential of leukemic-MEPs in mouse models and in human AML with PRDM16 rearrangement. Our study demonstrates that oncogenic PRDM16 expression converts the fate of MEPs to a malignant myeloid fate by activating myeloid master transcription factors.
2019-03-01 | GSE119299 | GEO
Project description:Oncogenic mutations confer aberrant replicative capacity to cells with little or no replicative capacity, generating cancer stem cells that perpetuate the tumor through extensive self-replication and differentiation blockade. However, whether oncogenes disrupt the cellular identity of cancer stem cell by altering the developmental potential is unknown. Fate conversion has been demonstrated by ectopic expression of master transcriptional regulators, such as PU.1 and C/EBPα that confers myeloid cell fate to other cell types, and PRDM16 that confers brown adipose fate to white adipocytes or myoblasts. Here we show that a transcriptional regulator overexpressed in human myeloid malignancies, PRDM16s, causes oncogenic fate conversion, by transforming cells fated to form platelets and erythrocytes into myeloid leukemia-initiating cells (LICs). Prdm16s expression in murine hematopoietic progenitor cells caused a myelodysplastic syndrome (MDS)-like disease that progressed to acute myelogenous leukemia (AML). The myeloid diseases caused by Prdm16s exhibited expansion of megakaryocyte-erythroid progenitors (MEPs) but not granulocyte-macrophage progenitors. MEPs from Prdm16s-induced leukemia possessed LIC potential, and expression of Prdm16s in normal MEPs was sufficient to convert them to myeloid LICs and blocked megakaryocytic/erythroid potential. Prdm16s induced the expression of myeloid master regulators, including PU.1 and C/EBPα, by interacting with their super enhancers. Ablation of myeloid master regulators attenuated the myeloid potential and reinstalled the megakaryocytic/erythroid potential of leukemic-MEPs in mouse models and in human AML with PRDM16 rearrangement. Our study demonstrates that oncogenic PRDM16 expression converts the fate of MEPs to a malignant myeloid fate by activating myeloid master transcription factors.
2019-03-01 | GSE119298 | GEO
Project description:Oncogenic mutations confer aberrant replicative capacity to cells with little or no replicative capacity, generating cancer stem cells that perpetuate the tumor through extensive self-replication and differentiation blockade. However, whether oncogenes disrupt the cellular identity of cancer stem cell by altering the developmental potential is unknown. Fate conversion has been demonstrated by ectopic expression of master transcriptional regulators, such as PU.1 and C/EBPα that confers myeloid cell fate to other cell types, and PRDM16 that confers brown adipose fate to white adipocytes or myoblasts. Here we show that a transcriptional regulator overexpressed in human myeloid malignancies, PRDM16s, causes oncogenic fate conversion, by transforming cells fated to form platelets and erythrocytes into myeloid leukemia-initiating cells (LICs). Prdm16s expression in murine hematopoietic progenitor cells caused a myelodysplastic syndrome (MDS)-like disease that progressed to acute myelogenous leukemia (AML). The myeloid diseases caused by Prdm16s exhibited expansion of megakaryocyte-erythroid progenitors (MEPs) but not granulocyte-macrophage progenitors. MEPs from Prdm16s-induced leukemia possessed LIC potential, and expression of Prdm16s in normal MEPs was sufficient to convert them to myeloid LICs and blocked megakaryocytic/erythroid potential. Prdm16s induced the expression of myeloid master regulators, including PU.1 and C/EBPα, by interacting with their super enhancers. Ablation of myeloid master regulators attenuated the myeloid potential and reinstalled the megakaryocytic/erythroid potential of leukemic-MEPs in mouse models and in human AML with PRDM16 rearrangement. Our study demonstrates that oncogenic PRDM16 expression converts the fate of MEPs to a malignant myeloid fate by activating myeloid master transcription factors.
2019-03-01 | GSE119302 | GEO
Project description:Oncogenic mutations confer aberrant replicative capacity to cells with little or no replicative capacity, generating cancer stem cells that perpetuate the tumor through extensive self-replication and differentiation blockade. However, whether oncogenes disrupt the cellular identity of cancer stem cell by altering the developmental potential is unknown. Fate conversion has been demonstrated by ectopic expression of master transcriptional regulators, such as PU.1 and C/EBPα that confers myeloid cell fate to other cell types, and PRDM16 that confers brown adipose fate to white adipocytes or myoblasts. Here we show that a transcriptional regulator overexpressed in human myeloid malignancies, PRDM16s, causes oncogenic fate conversion, by transforming cells fated to form platelets and erythrocytes into myeloid leukemia-initiating cells (LICs). Prdm16s expression in murine hematopoietic progenitor cells caused a myelodysplastic syndrome (MDS)-like disease that progressed to acute myelogenous leukemia (AML). The myeloid diseases caused by Prdm16s exhibited expansion of megakaryocyte-erythroid progenitors (MEPs) but not granulocyte-macrophage progenitors. MEPs from Prdm16s-induced leukemia possessed LIC potential, and expression of Prdm16s in normal MEPs was sufficient to convert them to myeloid LICs and blocked megakaryocytic/erythroid potential. Prdm16s induced the expression of myeloid master regulators, including PU.1 and C/EBPα, by interacting with their super enhancers. Ablation of myeloid master regulators attenuated the myeloid potential and reinstalled the megakaryocytic/erythroid potential of leukemic-MEPs in mouse models and in human AML with PRDM16 rearrangement. Our study demonstrates that oncogenic PRDM16 expression converts the fate of MEPs to a malignant myeloid fate by activating myeloid master transcription factors.
2019-03-01 | GSE119301 | GEO
Project description:PU.1 is a prototype master transcription factor (TF) of hematopoietic cell differentiation with diverse roles in different lineages. Analysis of its genome-wide binding pattern across PU.1 expressing cell types revealed manifold cell type-specific binding patterns. They are not consistent with the epigenetic and chromatin constraints to PU.1 binding observed in vitro, suggesting that PU.1 requires auxiliary factors to access DNA in vivo. Using a model of transient mRNA expression we show that PU.1 induction leads to the extensive remodeling of chromatin, redistribution of partner transcription factors and rapid initiation of a myeloid gene expression program in heterologous cell types. By probing PU.1 mutants for defects in chromatin access and screening for PU.1 proximal proteins in vivo, we found that its N-terminal acidic domain was required for the recruitment of SWI/SNF remodeling complexes, de novo chromatin access and stable binding as well as the redistribution of partner TFs.
2019-11-20 | PXD013167 | Pride
Project description:CARM1 is essential for the development and maintenance of myeloid neoplasms. We found that non-phosphorylatable CARM1 mutation impairs cell cycle progression, induces apoptosis, and downregulates stemness in JAK2-mutant cell lines, suggesting that CARM1 phosphorylation is required for maximal proliferation of myeloid neoplasms.
2024-04-03 | GSE174432 | GEO
Project description:Dendritic cells (DCs) are essential regulators of immune responses; however, transcriptional mechanisms establishing DC lineage commitment are poorly defined. Here we report that the PU.1 transcription factor induces specific remodeling of the higher-order chromatin structure at the Interferon Regulatory Factor-8 (Irf8) gene to initiate DC fate choice. Generation of an Irf8 reporter mouse enabled us to pinpoint an initial progenitor stage at which DCs separate from other myeloid lineages in the bone marrow. In the absence of Irf8, this progenitor undergoes DC-to-neutrophil reprogramming, indicating that DC commitment requires an active, Irf8-dependent escape from alternative myeloid lineage potential. Mechanistically, myeloid Irf8 expression depends on high PU.1 levels, resulting in local chromosomal looping and activation of a lineage- and developmental stage-specific cis-enhancer. These data delineate PU.1 as a concentration-dependent rheostat of myeloid lineage selection by controlling long-distance contacts between regulatory elements, and suggest that specific higher-order chromatin remodeling at the Irf8 gene determines DC differentiation. Mature macrophages, Granulocytes and DCs were isolated from wildtype mouse spleens for successive RNA extraction and hybridization on Affymetrix microarrays. 3 different pools, each consisting of splenic cells from 5 mice were prepared. Cell populations were isolated by flow cytometry. MDPs were isolated from Wildtype and IRF8 deficient bonemarrow by flowcytometry, again creating 3 biological replicates, each consisting of pooled cells from 5 mice. Differential gene expression between wildtype and IRF8 deficient MDPs was subgrouped into macrophage, granuloctic and DC signatures, derived from expression data of these cell populations.
2013-04-27 | E-GEOD-45467 | biostudies-arrayexpress