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Dual role of EZH2 on megakaryocyte differentiation, ChIP-seq analysis at different stages of megakaryocyte maturation

ABSTRACT: Dual role of EZH2 on megakaryocyte differentiation, ChIP-seq analysis at different stages of megakaryocyte maturation

PROVIDER: PRJEB35897 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR3772310_1.fastq.gz	Fastqsanger.gz
	ERR3772310_2.fastq.gz	Fastqsanger.gz
	ERR3772320_1.fastq.gz	Fastqsanger.gz
	ERR3772320_2.fastq.gz	Fastqsanger.gz
	ERR3772311_1.fastq.gz	Fastqsanger.gz

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Dual role of EZH2 on megakaryocyte differentiation, ChIP-seq analysis at different stages of megakaryocyte maturation

Project description:EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss of function mutations have been found in myeloproliferative neoplasms, more particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and shRNA induces MK commitment by accelerating lineage marker acquisition without change in proliferation. Later in differentiation, EZH2 inhibition blocks proliferation and endomitosis and decreases proplatelet formation. EZH2 inhibitors similarly reduce polyploidization and proplatelet formation of JAK2V617F MK. In transcriptome profiling, the defect in proplatelet formation was associated with an aberrant actin cytoskeleton regulation pathway, whereas polyploidization was associated with an inhibition of expression for a set of genes involved in DNA replication and repair, and an upregulation of CDK inhibitors, more particularly CDKN1A and CDKN2D. The knockdown of CDKN1A and/or CDKN2D could partially rescue the percentage of polyploid MKs. However only CDKN1A was regulated by H3K27me3 suggesting that EZH2 controls MK polyploidization through a direct regulation of CDKN1A and indirectly of CDKN2D.

2021-03-31 | E-MTAB-8611 | biostudies-arrayexpress

Dual role of EZH2 on megakaryocyte differentiation, analysis at different stages of maturation at day 9 of culture

2021-11-02 | E-MTAB-8610 | biostudies-arrayexpress

Dual role of EZH2 in megakaryocyte differentiation.

Project description:EZH2, the enzymatic component of PRC2, has been identified as a key factor in hematopoiesis. EZH2 loss-of-function mutations have been found in myeloproliferative neoplasms, particularly in myelofibrosis, but the precise function of EZH2 in megakaryopoiesis is not fully delineated. Here, we show that EZH2 inhibition by small molecules and short hairpin RNA induces megakaryocyte (MK) commitment by accelerating lineage marker acquisition without change in proliferation. Later in differentiation, EZH2 inhibition blocks proliferation and polyploidization and decreases proplatelet formation. EZH2 inhibitors similarly reduce MK polyploidization and proplatelet formation in vitro and platelet levels in vivo in a JAK2V617F background. In transcriptome profiling, the defect in proplatelet formation was associated with an aberrant actin cytoskeleton regulation pathway, whereas polyploidization was associated with an inhibition of expression of genes involved in DNA replication and repair and an upregulation of cyclin-dependent kinase inhibitors, particularly CDKN1A and CDKN2D. The knockdown of CDKN1A and to a lesser extent CDKN2D could partially rescue the percentage of polyploid MKs. Moreover, H3K27me3 and EZH2 chromatin immunoprecipitation assays revealed that CDKN1A is a direct EZH2 target and CDKN2D expression is not directly regulated by EZH2, suggesting that EZH2 controls MK polyploidization directly through CDKN1A and indirectly through CDKN2D.

| S-EPMC8554649 | biostudies-literature

Single-cell RNA sequencing reveals the novel role of Ezh2 in NK cell maturation and function

Project description:Our previous work indicated that the Enhancer of Zeste Homolog 2 (Ezh2) is a negative regulator of NK cell early differentiation and function by trimethylation of histone H3 lysine 27 (H3K27me3). Here, we deleted Ezh2 from immature NK and downstream progeny to explore its role in NK cell maturation by single-cell RNA sequencing (scRNA-seq). We identified six distinct NK stages based on transcriptional signature during the maturation of NK cells. Conditional deletion of Ezh2 in NK cells resulted in the maturation trajectory of NK cell arrested in CD11b SP stage 5 which is clustered with genes related to activating function of NK cells. Mechanistically, we speculated that Ezh2 plays a critical role in NK development by activating gene expression of the AP-1 superfamily independent of PRC2 function. Our results implied a novel role for the Ezh2-AP-1-Klrg1 axis to alter NK cell maturation trajectory and NK cell-mediated cytotoxicity.

2021-07-07 | GSE179186 | GEO

Dual role of EZH2 on megakaryocyte differentiation, analysis on mature megakaryocytes at day 13 of culture

2021-11-02 | E-MTAB-8609 | biostudies-arrayexpress

MKL1 augments megakaryocyte maturation by enhancing the SRF regulatory axis

Project description:MKL1 augments megakaryocyte maturation by enhancing the SRF regulatory axis

| PRJNA445459 | ENA

Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation [D7-EZH2-RNAseq]

Project description:To demonstrate that EZH2 regulates human erythropoiesis in a stage-specific, dual-function manner by catalyzing histone and non-histone methylation, we performed RNA-seq and ChIP-seq.

2024-01-01 | GSE222114 | GEO

Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation [D15-EZH2-RNAseq]

Project description:To demonstrated that EZH2 regulates human erythropoiesis in a stage-specific, dual-function manner by catalyzing histone and non-histone methylation,We performed RNA-seq and ChIP-seq.

2024-01-01 | GSE221932 | GEO

Dual inhibition of EZH2 and G9a suppresses multiple myeloma cell proliferation by regulating interferon signal and IRF4-MYC axis

Project description:Epigenetic mechanisms including histone modifications play key roles in the pathogenesis of multiple myeloma (MM). We have previously shown that a histone H3 lysine 27 (H3K27) methyltransferase EZH2 and a H3K9 methyltransferase G9a are potential therapeutic targets in MM. Recent studies suggested that EZH2 and G9a cooperate to regulate gene expression. We thus aimed to evaluate the anti-tumor effect by dual targeting of EZH2 and G9a in MM. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed myeloma cell proliferation through inducing cell cycle arrest and apoptosis in vitro. Dual inhibition of EZH2 and G9a also repressed xenograft formation by myeloma cells in vivo. Higher expression levels of EZH2 and EHMT2, which encodes G9a, are significantly associated with poorer prognosis in MM patients, respectively. Microarray analysis revealed that EZH2/G9a inhibition significantly upregulated interferon (IFN)-stimulated genes and suppressed IRF4-MYC axis genes in myeloma cells. Notably, we found increased expression and reduced H3K27/H3K9 methylation levels of endogenous retrovirus (ERV) genes in myeloma cells with the dual inhibition, suggesting that activation of the ERV genes may cause the IFN response. These results suggest that dual targeting of EZH2 and G9a may be a novel therapeutic strategy in MM.

2021-01-27 | GSE155135 | GEO

Sp1/Sp3 transcription factors regulate hallmarks of megakaryocyte maturation, and platelet formation and function

Project description:Sp1 and Sp3 belong to the Specificity proteins (Sp)/Krüppel-like transcription factor family. They are closely related, ubiquitously expressed and recognize G-rich DNA motifs. They are thought to regulate generic processes such as cell cycle and growth control, metabolic pathways and apoptosis. Ablation of Sp1 or Sp3 in mice is lethal, and combined haploinsufficiency results in hematopoietic defects during the fetal stages. Here, we show that in adult mice conditional ablation of either Sp1 or Sp3 has minimal impact on hematopoiesis, while the simultaneous loss of Sp1 and Sp3 results in severe macrothrombocytopenia and platelet dysfunction. We employed flow cytometry, cell culture and electron microscopy and show that although megakaryocyte numbers are normal in bone marrow and spleen, they display a less compact demarcation membrane system and a striking inability to form proplatelets. Through megakaryocyte transcriptomics and platelet proteomics we identified several cytoskeleton-related proteins and downstream effector kinases, including Mylk, that were downregulated upon Sp1/Sp3 depletion, providing an explanation for the observed defects in megakaryopoiesis. We show that Mylk is required for proplatelet formation and stabilization and for ITAM-receptor mediated platelet aggregation. Our data highlights the specific vs generic role of these ubiquitous transcription factors in the highly specialized megakaryocytic lineage. Megakaryocyte mRNA profiles of Sp1fl/fl::Sp3fl/fl (WTlox) and Pf4-Cre::Sp1fl/fl::Sp3fl/fl (dKO) mice were generated by deep sequencing, in triplicate.

2014-12-18 | E-GEOD-58707 | biostudies-arrayexpress

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