PRMT5 methylome profiling uncovers a direct link to splicing regulation in human acute myeloid leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA532395 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8882570.fastq.gz | Fastqsanger.gz | |||
| SRR8882571.fastq.gz | Fastqsanger.gz | |||
| SRR8882572.fastq.gz | Fastqsanger.gz | |||
| SRR8882573.fastq.gz | Fastqsanger.gz | |||
| SRR8882574.fastq.gz | Fastqsanger.gz |
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Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and two PRMT5 inhibitors are currently in clinical trials for a range malignancies. Despite the recognized therapeutic potential, it is unclear which PRMT5 functions underlie its oncogenic activity. In this study, we aimed to further understand the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using cutting-edge proteomics techniques we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 directly regulates SRSF1 activity in leukemia, and they provide potential biomarkers for the treatment response to PRMT5 inhibitors.
2019-08-21 | PXD014792 | Pride
Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and two PRMT5 inhibitors are currently in clinical trials for a range malignancies. Despite the recognized therapeutic potential, it is unclear which PRMT5 functions underlie its oncogenic activity. In this study, we aimed to further understand the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using cutting-edge proteomics techniques we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 directly regulates SRSF1 activity in leukemia, and they provide potential biomarkers for the treatment response to PRMT5 inhibitors.
2019-11-08 | PXD013611 | Pride
Project description:Protein arginine methyltransferase 5 (PRMT5) belongs to the class II arginine methyltransferases and catalyzes monomethylation and symmetrical dimethylation of arginines on proteins. It has recently emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for a range of malignancies. In this study, we aimed to further elucidate the role of PRMT5 in acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 as well as a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. By using multiplexed quantitative proteomics, we identified PRMT5 substrates and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5. Consistent with this, we found that loss of PRMT5 led to changes in alternative splicing. This analysis revealed multiple affected essential genes, linking PRMT5 activity to its loss of function phenotype. Our results show that PRMT5 regulates binding of SRSF1 to mRNAs and proteins in leukemia and provide potential biomarkers for the treatment response to PRMT5 inhibitors.
2019-08-20 | GSE129652 | GEO
Project description:Protein arginine methyltransferase 5 (PRMT5) has emerged as a promising cancer drug target, and three PRMT5 inhibitors are currently in clinical trials for multiple malignancies. In this study, we investigated the role of PRMT5 in human acute myeloid leukemia (AML). Using an enzymatic dead version of PRMT5 and a PRMT5-specific inhibitor, we demonstrated the requirement of the catalytic activity of PRMT5 for the survival of AML cells. We then identified PRMT5 substrates using multiplexed quantitative proteomics and investigated their role in the survival of AML cells. We found that the function of the splicing regulator SRSF1 relies on its methylation by PRMT5 and that loss of PRMT5 leads to changes in alternative splicing of multiple essential genes. Our study proposes a mechanism for the requirement of PRMT5 for leukemia cell survival and provides potential biomarkers for the treatment response to PRMT5 inhibitors.
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Project description:This SuperSeries is composed of the following subset Series: GSE35911: Reversal of Aberrant Cancer Methylome and Transcriptome upon Direct Reprogramming of Lung Cancer Cells [Expression] GSE35912: Reversal of Aberrant Cancer Methylome and Transcriptome upon Direct Reprogramming of Lung Cancer Cells [Methylation] Refer to individual Series
2012-08-27 | E-GEOD-35913 | biostudies-arrayexpress
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Project description:Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which entails comprehensive erasure of DNA methylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs caused complete male and female sterility, which is preceded by upregulation of LINE1 and IAP transposons and DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation and early embryonic lethality. We detected the PRMT5-catalysed repressive H2A/H4R3me2s modification on LINE1 and IAP in early wildtype PGCs, directly implicating this mark in the maintenance of transposon silencing during DNA hypomethylation. PRMT5 subsequently translocates back to the cytoplasm of PGCs to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA re-methylation. Thus, PRMT5 has a novel direct role in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation PGCs mRNA profiles of embryonic day 11.5 dpc control (Blimp1Cre;Prmt5flox/+) and Prmt5 germ cell knockout (Blimp1Cre;Prmt5 flox/flox) were generated by deep sequencing (SOLiD next generation sequencing).
2014-09-09 | E-GEOD-61216 | biostudies-arrayexpress
Project description:Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which entails comprehensive erasure of DNA methylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs caused complete male and female sterility, which is preceded by upregulation of LINE1 and IAP transposons and DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation and early embryonic lethality. We detected the PRMT5-catalysed repressive H2A/H4R3me2s modification on LINE1 and IAP in early wildtype PGCs, directly implicating this mark in the maintenance of transposon silencing during DNA hypomethylation. PRMT5 subsequently translocates back to the cytoplasm of PGCs to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA re-methylation. Thus, PRMT5 has a novel direct role in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation PGCs mRNA profiles of embryonic day 11.5 dpc control (Blimp1Cre;Prmt5flox/+) and Prmt5 germ cell knockout (Blimp1Cre;Prmt5 flox/flox) were generated by deep sequencing (SOLiD next generation sequencing).
2014-11-14 | E-GEOD-60875 | biostudies-arrayexpress
Project description:Examining the effects of PRMT5 loss on the gene expression profile of hematopoietic stem and progenitor cells We established the PRMT5 conditional KO mice, and bred the mice with Mx1 cre transgenic mice to delete PRMT5 in hematopoietic cells. We isolated hematopoetic stem and progenitor cells 3 days after PRMT5 deletion, and examined the gene expression files using RNA-sequencing.
2015-07-15 | E-GEOD-69937 | biostudies-arrayexpress
Project description:PRMT5 is important for gliomas, however its physiological function in oligodendrocyte progenitors (OPCs), remains poorly understood. Here we report PRMT5 to be responsible for symmetric di-methylation of histone H4R3 (H4R3me2s) in OPC. PRMT5 depletion via CRISPR/Cas9 decreased H4R3me2s, altered the OPC transcriptome, and decreased OPC survival. Strikingly, these changes were associated with a marked increase of H4K5ac in OPC, but not in gliomas. Consistently, ChIP-sequencing analysis revealed increased genome-wide distribution of H4K5ac in PRMT5 knockout cells. In vitro acetylation assays demonstrated reciprocal inhibition between symmetric arginine methylation and lysine acetylation. Low H4R3me2s and high H4K5ac levels were also detected in OPC in mice with lineage-specific ablation of Prmt5 (Olig1-Cre;Prmt5fl/fl), resulting in severely impaired developmental myelination. Importantly, pharmacological inhibition of acetyltransferase activity partially rescued the effect of Prmt5 deletion on oligodendrocyte-specific gene transcripts. Collectively, we identify PRMT5 as a critical modulator of histone acetylation and OPC differentiation in early developmental myelination.
2018-06-02 | GSE94067 | GEO