Arginine methylationof the p30 C/EBPα oncoprotein regulates progenitor proliferationand myeloid differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1107559 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28889335_1.fastq.gz | Fastqsanger.gz | |||
| SRR28889335_2.fastq.gz | Fastqsanger.gz | |||
| SRR28889336_1.fastq.gz | Fastqsanger.gz | |||
| SRR28889336_2.fastq.gz | Fastqsanger.gz | |||
| SRR28889337_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 40 |
Similar Datasets
Project description:The transcription factor CCAAT enhancer binding protein alpha (C/EBPα) is a master regulator of myelopoiesis. CEBPA encodes a long (p42) and a truncated (p30) protein isoform from a single mRNA. Mutations that abnormally enhance expression of p30 are associated with acute myelogenous leukemia (AML). We show by mutational analysis that three highly conserved arginine residues (R140,147,154) located at the p30 C/EBPα N-terminus, previously found to be methylated, are involved in myeloid lineage commitment, progenitor proliferation, and differentiation. The conservative amino acid substitution with lysine that retains the amino acid side chain charge enhanced progenitor proliferation, while a non-conservative substitution with uncharged side chains (alanine or leucine) impaired proliferation and enhanced granulopoietic differentiation. Analysis of protein-protein interactions (PPI) suggested that arginine methylation of p30 C/EBPα differentially determines its capacity to interact with SWI/SNF and MLL complexes. Pharmacological targeting of p30 C/EBPα arginine methylation may have clinical relevance in myeloproliferative and inflammatory diseases, in neutropenia, and in leukemic stem cells.
2024-11-20 | GSE266544 | GEO
Project description:CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.
2023-11-08 | GSE243422 | GEO
Project description:CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.
2023-11-08 | GSE243423 | GEO
Project description:C/EBPα is an essential transcription factor involved in regulating the expression or function of certain cell-cycle regulators. However, little is known about the role of methylation in regulating the antiproliferation activity of C/EBPα. Here, we report that knockdown of protein arginine methyltransferases 1 (PRMT1) leads to cellular growth arrest accompanied by a decrease in Cyclin D1 gene expression in breast cancer cells. Furthermore, we reveal that C/EBPα is methylated by PRMT1 at three arginine residues (R35, R156, and R165), which impairs the interaction of C/EBPα with HDAC3 and modulates the transcription activity of C/EBPα and Cyclin D1 gene expression. PRMT1 is upregulated in human breast cancer, and elevated PRMT1 is correlated with cancer malignancy. Most importantly, a specific inhibitor of PRMT1 significantly impedes the growth of cancer cells from triple-negative breast cancer patients. Our data demonstrate that high expression of PRMT1 promotes the expression of Cyclin D1 through methylation of C/EBPα to interfere with the repressive function of HDAC3, which leads to rapid growth of tumor cells during the pathogenesis of breast cancer. This evidence that PRMT1 mediates C/EBPα methylation sheds light on a novel therapeutic pathway for breast cancer.
2020-04-05 | GSE121168 | GEO
Project description:Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ~10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but down-stream targets relevant for leukemogenesis are not known. Here we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia initiating cells (LICs) from both Sox4 overexpression and murine mutant C/EBPα AML models clustered together, but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemias with a distinct LIC phenotype.
2013-03-23 | GSE45430 | GEO
Project description:Accumulating evidences indicate that different long non-coding RNAs (lncRNAs) might play a relevant role in tumorigenesis, with their expression and function already associated to cancer development and progression. CCAAT/enhancer-binding protein-α (CEBPA) is a critical regulator of myeloid differentiation whose inactivation contributes to the development of acute myeloid leukemia (AML). Mutations in C/EBPα occur in around 10% of AML cases, leading to the expression of a 30-kDa dominant negative isoform (C/EBPα-p30). In this study, we identified the oncogenic urothelial carcinoma associated 1 (UCA1) lncRNA as a novel target of the C/EBPα-p30. We show that wild-type C/EBPα and C/EBPα-p30 isoform can bind the UCA1 promoter but have opposite effects on UCA1 expression. While wild-type C/EBPα represses, C/EBPα-p30 can induce UCA1 transcription. Notably, we also show that UCA1 expression increases in cytogenetically normal AML cases carrying biallelic CEBPA mutations. Furthermore, we demonstrate that UCA1 sustains proliferation of AML cells by repressing the expression of the cell cycle regulator p27kip1. Thus, we identified, for the first time, an oncogenic lncRNA functioning in concert with the dominant negative isoform of C/EBPα in AML.
| S-EPMC4621908 | biostudies-literature
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: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 | GSE229072 | GEO