RNA deep sequencing to compare genome-wide differences between PRMT5/knockdown and control AML cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75215 | GEO | 2016/05/19
SECONDARY ACCESSION(S): PRJNA302812
REPOSITORIES: GEO
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Project description:We report the pro-leukemic activities of PRMT5 in AML partly via modulating the transcription of key genes. The goal of this experiment is to confirm the changes observed in expression of genes targeted by PRMT5 activities. RNA Deep sequencing was employed to validate and reproduce the changes measured by quantitative reverse transcription polymerase chain reaction (qRTâPCR) techniques. Total RNA samples from MV4-11 cell line (FLT3-ITD AML) following PRMT5 knockdown using specific short hairpin RNA (shRNA) was used to compare gene expression pattern between PRMT5/Knockdown and control (control: MV4-11 cells transduced with scramble control).
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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.
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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.
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Project description:Patients suffering from chronic lymphocytic leukemia (CLL) display highly diverse clinical courses ranging from indolent cases to aggressive disease with genetic and epigenetic features resembling this diversity. Here, we developed a comprehensive approach combining a variety of molecular and clinical data to identify translocation events disrupting long-range chromatin interactions and causing cancer-relevant transcriptional deregulation. Thereby, we identified a B cell specific cis-regulatory element restricting the expression of genes in the associated locus, including PRMT5 and DAD1, two factors with oncogenic potential. Examining the role of PRMT5 in CLL identified transcriptional programs associated with pathways of stress tolerance and growth support, maintaining MYC-driven gene expression in vivo and in vitro. Conversely, inhibition of PRMT5 impairs factors involved in DNA-repair and sensitizes cells for apoptosis. Finally, we show that artificial deletion of the regulatory element from its endogenous context resulted in upregulation of corresponding genes, including PRMT5. Furthermore, such disruption renders PRMT5 transcription vulnerable to additional stimuli and subsequently also alters the expression of downstream PRMT5 targets.
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Project description:Patients suffering from chronic lymphocytic leukemia (CLL) display highly diverse clinical courses ranging from indolent cases to aggressive disease with genetic and epigenetic features resembling this diversity. Here, we developed a comprehensive approach combining a variety of molecular and clinical data to identify translocation events disrupting long-range chromatin interactions and causing cancer-relevant transcriptional deregulation. Thereby, we identified a B cell specific cis-regulatory element restricting the expression of genes in the associated locus, including PRMT5 and DAD1, two factors with oncogenic potential. Examining the role of PRMT5 in CLL identified transcriptional programs associated with pathways of stress tolerance and growth support, maintaining MYC-driven gene expression in vivo and in vitro. Conversely, inhibition of PRMT5 impairs factors involved in DNA-repair and sensitizes cells for apoptosis. Finally, we show that artificial deletion of the regulatory element from its endogenous context resulted in upregulation of corresponding genes, including PRMT5. Furthermore, such disruption renders PRMT5 transcription vulnerable to additional stimuli and subsequently also alters the expression of downstream PRMT5 targets.
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