Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [ChIP-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243423 | GEO | 2023/11/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [RNA-seq]

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

Arginine methylationof the p30 C/EBPα oncoprotein regulates progenitor proliferationand myeloid differentiation

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

HSD17B13 liquid-liquid phase separation activates autocrine platelet-activating factor signaling in NASH

Project description:Loss-of-function variants in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) are associated with decreased inflammation in human chronic liver disease. The underlying mechanism by which HSD17B13 promotes liver inflammation remains largely elusive. Here we find that HSD17B13 undergoes liquid-liquid phase separation (LLPS) around lipid droplets (LDs) in the liver of NASH patients. Dimerization of HSD17B13 drives LLPS formation and regulates its enzyme activity. HSD17B13 LLPS promotes leukocyte adhesion and fibrinogen expression in hepatocytes via activating autocrine platelet activating factor (PAF) signaling. Importantly, adeno-associated viral (AAV)-mediated xeno-expression of human HSD17B13 promotes liver inflammation in Hsd17b13-/- mice induced by high fat diet/carbon tetrachloride treatment. In conclusion, HSD17B13 LLPS triggers liver inflammation via promoting PAF-mediated leukocyte adhesion. Targeting HSD17B13 phase transition would be a promising approach to treat liver inflammation in chronic liver disease.

2024-12-19 | GSE238060 | GEO

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation

Project description:Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation

| PRJNA1018468 | ENA

Study on the effect and mechanism of c-Maf liquid-liquid separation in promoting MM cellular proliferation and drug resistance through Mtbp/c-Myc axis

Project description:Previous experiments have demonstrated that c-Maf can undergo liquid-liquid phase separation (LLPS) in MM. In order to search for the downstream target genes of c-Maf based on its LLPS regulation, we successfully constructed three kinds of cells with EV, c-Maf and already c-Maf-IDR mutation, and simultaneously subjected the three kinds of cells to ChIP sequencing (selecting the FLAG-tagged antibody), and then analysed them for the differential genes, thus screening the downstream targets of c-Maf based on its LLPS regulation.

2024-08-31 | GSE264392 | GEO

CEBPA-mutated leukemia is sensitive to genetic and pharmacological inhibition of the MLL complex

Project description:The gene encoding the transcription factor C/EBPα is mutated in 10-15% of all patients with de novo acute myeloid leukemia (AML). N-terminal CEBPA mutations cause selective ablation of full-length C/EBPα without affecting the expression of a shorter oncogenic isoform, termed p30. The mechanistic basis of p30-induced leukemogenesis is not well understood. Here, we show that the SET/MLL histone methyltransferase complex represents a critical actionable vulnerability in CEBPA-mutated AML. The oncogenic C/EBPα p30 isoform and MLL show global co-localization on chromatin and core SET/MLL complex components exhibit robust physical interaction with p30. We also show that C/EBPα p30-expressing cells require the expression of an intact MLL protein, as targeted CRISPR/Cas9-mediated mutagenesis results in proliferation arrest and myeloid differentiation. In line with this, CEBPA-mutated hematopoietic progenitor cells are hypersensitive to pharmacological inhibition of the SET/MLL complex. SET/MLL complex inhibition impairs proliferation, induces cell cycle arrest and causes apoptosis in mouse and human AML cells with CEBPA mutations. Global analysis of gene expression changes shows that inhibitor treatment restores myeloid differentiation potential in CEBPA-mutated cells. Finally, we identify the transcription factor GATA2 as a direct critical target of the cooperative gene regulation between p30 and MLL in CEBPA-mutated AML. Taken together, we show that C/EBPα p30 requires the SET/MLL complex to regulate oncogenic gene expression and that CEBPA-mutated AML is hypersensitive to perturbation of the SET/MLL complex. These findings expand our understanding of CEBPA-mutated AML and identify the SET/MLL complex as a potential therapeutic target in this disease.

2019-01-29 | GSE117780 | GEO

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [RNA-seq]

Project description:Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [RNA-seq]

| PRJNA1018475 | ENA

Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [ChIP-seq]

Project description:Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation [ChIP-seq]

| PRJNA1018474 | ENA

Suppression of liquid-liquid phase separation by 1,6-hexanediol partially compromises the 3D genome organization in living cells

Project description:Liquid-liquid phase separation (LLPS) contributes to the spatial and functional segregation of molecular processes within the cell nucleus. However, the role played by LLPS in chromatin folding in living cells remains unclear. Here, using stochastic optical reconstruction microscopy (STORM) and Hi-C techniques, we studied the effects of 1,6-hexanediol (1,6-HD)- mediated LLPS disruption/modulation on higher-order chromatin organization in living cells. We found that 1,6-HD treatment caused the enlargement of nucleosome clutches and their more uniform distribution in the nuclear space. At a megabase-scale, chromatin underwent moderate but irreversible perturbations that resulted in the partial mixing of A and B compartments. The removal of 1,6-HD from the culture medium did not allow chromatin to acquire initial configurations, and resulted in more compact repressed chromatin than in untreated cells. 1,6-HD treatment also weakened enhancer-promoter interactions and TAD insulation but did not considerably affect CTCF-dependent loops. Our results suggest that 1,6-HD-sensitive LLPS plays a limited role in chromatin spatial organization by constraining its folding patterns and facilitating compartmentalization at different levels.

2021-03-22 | GSE138543 | GEO

First direct observation of elongated conformational states in alpha-synuclein upon liquid-liquid phase separation

Project description:α-Synuclein (α-syn) is an intrinsically disordered protein (IDP) that undergoes liquid-liquid phase separation (LLPS), fibrillation, and forms insoluble intracellular Lewy’s bodies in neurons, which are the hallmark of Parkinson’s Disease (PD). Neurotoxicity precedes the formation of aggregates and is probably related to LLPS of α-syn in the cell. The molecular mechanisms underlying the early stages of LLPS are still elusive. To obtain structural insights into α-syn upon LLPS, we take advantage of cross-linking/mass spectrometry (XL-MS) and introduced an innovative new approach, termed COMPASS (COMPetitive PAiring StatisticS). COMPASS unravels transient interactions between α-syn molecules in liquid droplets to derive structural information of α-syn upon LLPS. In this work, we show that the conformational ensemble of α-syn shifts towards more elongated conformational states upon LLPS. We obtain insights into the critical initial stages of PD and establish a novel mass spectrometry-based approach that will aid to solve open questions in LLPS structural biology.

2024-03-18 | PXD033205 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data