Prmt1 safeguards mouse embryonic stem cells against bias toward the extraembryonic endoderm cell fate via arginine methylation of Klf4
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ABSTRACT:
PROVIDER: PRJNA514313 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8429030_1.fastq.gz | Fastqsanger.gz | |||
| SRR8429030_2.fastq.gz | Fastqsanger.gz | |||
| SRR8429040_1.fastq.gz | Fastqsanger.gz | |||
| SRR8429040_2.fastq.gz | Fastqsanger.gz | |||
| SRR8429031_1.fastq.gz | Fastqsanger.gz |
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Project description:Heterogeneous gene expression is a characteristic feature of stem cells and is essential for steering lineage choices. However, the molecular mechanisms of heterogeneity remain largely unknown. Here, we report that depletion of protein arginine methyltransferase 1 (Prmt1) in mouse embryonic stem (ES) cells heterogeneously induces the expression of primitive endoderm (PrE) genes, consequently biasing the cells to fluctuate toward the extraembryonic endoderm stem (XEN) cell fate. Furthermore, the pluripotency factor Klf4 is arginine-methylated by Prmt1 at arginine 396 (R396), which is required for recruitment of the mSin3a/HDAC complex to silence PrE genes. Importantly, when methylation is disrupted by a Prmt1 knockout, a Prmt1 inhibitor, or a blocked methylation site in Klf4, ES cells are predisposed to XEN induction. Our data demonstrate the importance of Prmt1 in the fluctuating heterogeneity of ES cells and reveal a regulatory mechanism for cell fate decisions that is centered on Klf4 methylation mediated by Prmt1.
2021-12-27 | GSE124920 | GEO
Project description:PRMT1 is thought to be responsible for the majority of PRMT activity in Toxoplasma gondii, but its exact function is unknown. We generated T. gondii mutants lacking PRMT1 (∆prmt1) by deletion of the PRMT1 gene. ∆prmt1 parasites exhibit morphological defects during cell division and grow slowly, and this phenotype reverses in the complemented strain ∆prmt::PRMT1mRFP. PRMT1 localizes primarily in the cytoplasm with enrichment at the centrosome, and the strain lacking PRMT1 is unable to segregate progeny accurately. Unlike wild-type and complemented parasites, ∆prmt1 parasites have abnormal daughter buds, perturbed centrosome stoichiometry, and loss of synchronous replication. Whole genome expression profiling demonstrated differences in expression of cell cycle regulated genes in ∆prmt1 relative to the complemented ∆prmt1::PRMT1mRFP and parental wild-type strains, but these changes did not correlate with a specific block in cell cycle. Although PRMT1’s primary biological function was previously proposed to be methylation of histones, our genetic studies suggest that the most critical function of PRMT1 is within the centrosome as a regulator of daughter cell counting to assure the proper replication of the parasite. RNA samples were isolated in triplicates from RH-hxgprt parent strain (W), PRMT1 knockout (K) strain and PRMT1 knockout strain complemented with RFP-tagged PRMT1 protein (C). Parasites were grown for 32h at 37C. Samples were hybridized to the Toxoplasma gondii Affymetrix microarray (ToxoGeneChip: http://ancillary.toxodb.org/docs/Array-Tutorial.html). Hybridization data was preprocessed with Robust Multi-array Average (RMA) and normalized using per chip and per gene median polishing and analyzed using the software package GeneSpring GX (Agilent Technologies).
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Project description:Extraembryonic trophoblast stem cells (TSC) can be converted to induced pluripotent stem cells (TSC-iPSCs) by overexpressing Oct4, Sox2, Klf4 and cMyc.
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Project description:Transcriptional deregulation plays a major role in acute myeloid leukemia, identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence showing the functional involvement and therapeutic potentials of targeting PRMT1 with H4R3 methyltransferase activity in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C with H3K9 demethylase activity by chimeric transcription factors to mediate epigenetic reprogramming. Inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a novel and targetable epigenetic circuitry mediated by PRMT1 and KDM4C in acute leukemia.
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Project description:Here we determine the genome-wide binding sites of PRMT1 in primary human keratinocytes. We also investigated the impact of casein kinase inhibitor D4476 on PRMT1 genomic binding.
2018-02-02 | GSE110050 | GEO
Project description:PRMT1 is known as a regulator of immune function by directly interacting with interferon receptors, methylating STAT1, and promoting B cell and macrophage differentiation by methylating CDK4 or B cell antigen receptor However, the function of PRMT1 as a therapeutic target of cancer remains largely elusive, particularly for its role in cancer immunosurveillance. Here, we performed bulk RNA-seq for CT26, a mouse tumor cell line, after either knocking down of endogeneous Prmt1 or blocking PRMT1 by two specific inhibitors, namely MS023 and GSK3368715.
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Project description:Extraembryonic trophoblast stem cells (TSC) can be converted to induced pluripotent stem cells (TSC-iPSCs) by overexpressing Oct4, Sox2, Klf4 and cMyc. TSC lines were derived from mice harboring a doxycycline inducible Oct4 allele and an Oct4-GFP reporter that has been demonstrated to be activated in cells upon acquisition of pluripotency. Oct4-GFP-positive blastocysts were collected at 3.5 dpc and transduced with lentiviruses encoding doxycycline inducible Sox2, Klf4 and cMyc transgenes (4FTSC). 4FTSC lines were passaged 10 times to establish a population of constantly growing, self-renewing TSCs in the presence of FGF4 and fibroblast conditioned media. To induce lineage conversion, 4FTSCs were cultured under ESC/Lif conditions and doxycycline. After 28 days, several colonies displaying ESC-characteristic dome-shaped colony morphology and bright Oct4-GFP fluorescence could be detected. The 4FTSC-derived colonies were isolated mechanically, dissociated by trypsinization, and plated onto MEFs in ESC medium without doxycycline demonstrating the independence of exogenous factors. They will be called TSC-iPSCs (Trophoblast stem cell derived induced pluripotent stem cells). To examine if the extraembryonic lineage-specific mRNA profile was overcome, the gene-expression profiles of TSC-iPSCs and their parental 4FTSCs were analyzed by microarray analyses and compared to control ESCs.
2011-02-01 | E-GEOD-25872 | biostudies-arrayexpress
Project description:The interplay between multiple transcription factors precisely regulates eukaryotic transcription. Here, we report that the protein methyltransferases, MLL2 and PRMT1, interact directly and act collectively to regulate gene expression. PRMT1 binds to the N-terminal region of MLL2, considered an intrinsically disordered region, and methylates multiple arginine residues within its RGG/RG motifs. Notably, overexpression of PRMT1 decreased poly-ubiquitylation of MLL2, whereas mutations on methylation sites in MLL2 increased MLL2 poly-ubiquitylation, suggesting that PRMT1-mediated methylation stabilizes MLL2. MLL2 and PRMT1 cooperatively stimulated the expression of a chromosomal reporter gene in a PRMT1-mediated, MLL2-methylation–dependent manner. RNA-seq analysis found that MLL2 and PRMT1 jointly regulate the expression of genes involved in cell membrane and extracellular matrix functions, and depletion of either resulted in impaired cell migration and invasion. Our study provides evidence that PRMT1-mediated MLL2 methylation regulates MLL2 protein stability and the expression of their target genes.
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Project description:PRMT1 is thought to be responsible for the majority of PRMT activity in Toxoplasma gondii, but its exact function is unknown. We generated T. gondii mutants lacking PRMT1 (∆prmt1) by deletion of the PRMT1 gene. ∆prmt1 parasites exhibit morphological defects during cell division and grow slowly, and this phenotype reverses in the complemented strain ∆prmt::PRMT1mRFP. PRMT1 localizes primarily in the cytoplasm with enrichment at the centrosome, and the strain lacking PRMT1 is unable to segregate progeny accurately. Unlike wild-type and complemented parasites, ∆prmt1 parasites have abnormal daughter buds, perturbed centrosome stoichiometry, and loss of synchronous replication. Whole genome expression profiling demonstrated differences in expression of cell cycle regulated genes in ∆prmt1 relative to the complemented ∆prmt1::PRMT1mRFP and parental wild-type strains, but these changes did not correlate with a specific block in cell cycle. Although PRMT1’s primary biological function was previously proposed to be methylation of histones, our genetic studies suggest that the most critical function of PRMT1 is within the centrosome as a regulator of daughter cell counting to assure the proper replication of the parasite.
2015-09-18 | GSE73177 | GEO
Project description:This experiment is part of the FunGenES project (FunGenES - Functional Genomics in Embryonic Stem Cells partially funded by the 6th Framework Programme of the European Union, http://www.fungenes.org). The experiment was conducted at Inserm U846, Bron, France. Aim: Kru_ppel-like factors (Klf) 4 and 5 are two closely related members of the Klf family, known to play key roles in somatic cell reprogramming and in self-renewal of pluripotent stem cells. In this study, we focused on the functional divergence between Klf4 and Klf5. We showed that Klf4 and Klf5 regulate the expression of distinct subsets of genes. Klf4 negatively regulates the expression of endodermal markers, some of which encode transcription factors involved in the commitment of pluripotent system cells to endoderm differentiation. In contrast, Klf5 negatively regulates the expression of mesodermal markers, some of which controls commitment to the mesoderm lineage. Functional studies with reporter cell lines indicate that knockdown of Klf4 enhances differentiation toward visceral endoderm, mesendoderm, and definitive endoderm, whereas knockdown of Klf5 specifically enhances differentiation toward mesoderm. Thus, additive functions of Klf4 and Klf5 secure pluripotent stem cell propagation by inhibiting endoderm and mesoderm differentiation.
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