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Regulation of the core pre-mRNA splicing machinery by MYC and PRMT5 is essential to sustain lymphomagenesis [B-cells]

ABSTRACT: Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates gene expression, both positively and negatively. Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including PRMT5, an arginine methyltransferase, that methylates Sm proteins as an early step in lymphomagenesis. This coordinated regulatory effect is direct and is critical for snRNP biogenesis, the maintenance of effective mRNA splicing and cellular viability in cycling cells, in either fibroblasts or B-cells. mRNA profiles of wild type and pre-tumoral eu-myc mice by deep sequencing, in triplicate, using Illumina NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Diana Low

PROVIDER: E-GEOD-60188 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis.

Koh Cheryl M CM Bezzi Marco M Low Diana H P DH Ang Wei Xia WX Teo Shun Xie SX Gay Florence P H FP Al-Haddawi Muthafar M Tan Soo Yong SY Osato Motomi M Sabò Arianna A Amati Bruno B Wee Keng Boon KB Guccione Ernesto E

Nature 20150511 7558

Deregulated expression of the MYC transcription factor occurs in most human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis. Overexpressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates the expression of distinct subsets of genes. However, the critical effectors of MYC in tumorigenesis remain largely unknown. Here we show that during lymphomagenesis in Eµ-myc transgenic mice, ...[more]

PMID: 25970242

Similar Datasets

Regulation of the core pre-mRNA splicing machinery by MYC and PRMT5 is essential to sustain lymphomagenesis [fetal liver]

Project description:Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates gene expression, both positively and negatively. Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including PRMT5, an arginine methyltransferase, that methylates Sm proteins as an early step in lymphomagenesis. This coordinated regulatory effect is direct and is critical for snRNP biogenesis, the maintenance of effective mRNA splicing and cellular viability in cycling cells, in either fibroblasts or B-cells. Total RNA obtained from isolated fetal livers subjected to 24 hours of OHT or EtOH (control).

2015-05-19 | E-GEOD-61637 | biostudies-arrayexpress

Regulation of the core pre-mRNA splicing machinery by MYC and PRMT5 is essential to sustain lymphomagenesis [fetal liver]

2015-05-19 | GSE61637 | GEO

Regulation of the core pre-mRNA splicing machinery by MYC and PRMT5 is essential to sustain lymphomagenesis [B-cells]

2015-05-19 | GSE60188 | GEO

Tristetraprolin is a tumor suppressor that impairs Myc-induced lymphoma and abolishes the malignant state [Lymphoma].

Project description:Myc oncoproteins directly regulate transcription by binding to target genes, yet this only explains a fraction of the genes affected by Myc. mRNA turnover is controlled via AU-binding proteins (AUBPs) that recognize AU-rich elements (AREs) found within many transcripts. Analyses of precancerous and malignant Myc-expressing B cells revealed that Myc regulates hundreds of ARE-containing (ARED) genes and select AUBPs. Notably, Myc directly suppresses transcription of Tristetraprolin (TTP/ZFP36), an mRNA-destabilizing AUBP, and this circuit is also operational during B lymphopoiesis and IL7 signaling. Importantly, TTP suppression is a hallmark of cancers with MYC involvement, and restoring TTP impairs Myc-induced lymphomagenesis and abolishes maintenance of the malignant state. Further, there is a selection for TTP loss in malignancy; thus, TTP functions as a tumor suppressor. Finally, Myc/TTP-directed control of select cancer-associated ARED genes is disabled during lymphomagenesis. Thus, Myc targets AUBPs to regulate ARED genes that control tumorigenesis. Lymphomas collected from EÎ¼-Myc and EÎ¼-Myc;EÂµ-TTP-1 transgenic mice were investigated. These samples were used for subsequent RNA purification, labeling and hybridization to MOE430 2.0 Affymetrix arrays.

2012-08-01 | E-GEOD-37790 | biostudies-arrayexpress

Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery (RNA-Seq)

Project description:Protein Arginine MethylTransferase 5 (PRMT5) is known to mediate epigenetic control on chromatin and to functionally regulate components of the splicing machinery. In this study we show that selective deletion of PRMT5 in different organs leads to cell cycle arrest and apoptosis. At the molecular level, PRMT5 depletion results in reduced methylation of Sm proteins, aberrant constitutive splicing and in the Alternative Splicing (AS) of specific mRNAs. We identify Mdm4 as one of these mRNAs, which due to its weak 5’-Donor site, acts as a sensor of splicing defects and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in PRMT5 conditional knockout mice. Our data demonstrate a key role of PRMT5, together with p53, as guardians of the transcriptome. This will have fundamental implications in our understanding of PRMT5 activity, both in physiological conditions, as well as pathological conditions, including cancer and neurological diseases. Total RNA was extracted from control and Prmt5 depleted Neural Stem/Progenitors Cells (NPCs) and Mouse Embryonic Fibroblasts (MEFs). Prmt5 depleted cells were treated with 4-OHT 24 hours before splitting to induce PRMT5 knockout and final libraries were sequenced in triplicates on Illumina HiSeq 2000.

2013-09-13 | E-GEOD-45284 | biostudies-arrayexpress

The Sm protein methyltransferase PRMT5, is not required for primordial germ cell specification in mice

Project description:PRMT5 is a type II protein arginine methyltransferase with roles in stem cell biology, reprogramming, cancer and neurogenesis. During embryogenesis in the mouse it was hypothesized that PRMT5 functions with the master germline determinant BLIMP1 to promote primordial germ cell (PGC) specification. Using a Blimp1-Cre germline conditional knockout, we discovered that Prmt5 has no major role in murine germline specification, or the first global epigenetic reprogramming event involving depletion of cytosine methylation from DNA and histone H3 lysine 9 dimethylation from chromatin. Instead, we discovered that PRMT5 functions at the conclusion of PGC reprogramming I to promote proliferation, survival and expression of the gonadal germline program as marked by MVH. We show that PRMT5 regulates gene expression by promoting methylation of the Sm spliceosomal proteins, and significantly altering the spliced repertoire of RNAs in mammalian embryonic cells and primordial cells. Examination of transcriptional profile of iPHet (Control) vs. iPKO (Prmt5 knock out) 2i Embryonic Stem Cells

2014-12-05 | E-GEOD-63800 | biostudies-arrayexpress

Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-09-13 | E-GEOD-45285 | biostudies-arrayexpress

PRMT5 methyl proteomics in MiaPaca2 cells

Project description:Goal: To determine total PRMT5 methyl substrates and those that function through the novel substrate adaptor binding site

2022-06-13 | PXD019991 | Pride

Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis [ChIP-Seq]

Project description:The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci. Recent work suggested that rather than up- and down-regulating selected groups of genes, Myc targets all active promoters and enhancers in the genome (a phenomenon termed "invasion") and acts as a general amplifier of transcription. However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunoprecipitation and RNA expression profiles during B-cell lymphomagenesis in mice, in cultured B-cells and fibroblasts. Consistent with long-standing observations, we detected general increases in total RNA or mRNA copies per cell (hereby termed "amplification") when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response) or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amplification, Myc drove the differential expression of distinct subsets of target genes. Hence, while having the potential to interact with all active/poised regulatory elements in the genome, Myc does not directly act as a global transcriptional amplifier. Instead, our results imply that Myc activates and represses transcription of discrete gene sets, leading to changes in cellular state that can in turn feed back on global RNA production and turnover. Mapping c-Myc, RNAPII and H3K4me3, H3K4me1 and H3K27ac in four different models of Myc regulation Note: GEO Sample GSM894093 was used as input sample to generate processed data files P493.Myc.NoMyc.bed, P493.Myc.LowMyc.bed, P493.Myc.HighMyc.bed, P493.Myc.t1h.bed, P493.Myc.t24h.bed, P493.Pol2.NoMyc.bed, P493.Pol2.t24h.bed

2014-07-07 | E-GEOD-51004 | biostudies-arrayexpress

Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis [RNA-Seq]

Project description:The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci. Recent work suggested that rather than up- and down-regulating selected groups of genes, Myc targets all active promoters and enhancers in the genome (a phenomenon termed "invasion") and acts as a general amplifier of transcription. However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunoprecipitation and RNA expression profiles during B-cell lymphomagenesis in mice, in cultured B-cells and fibroblasts. Consistent with long-standing observations, we detected general increases in total RNA or mRNA copies per cell (hereby termed "amplification") when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response) or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amplification, Myc drove the differential expression of distinct subsets of target genes. Hence, while having the potential to interact with all active/poised regulatory elements in the genome, Myc does not directly act as a global transcriptional amplifier. Instead, our results imply that Myc activates and represses transcription of discrete gene sets, leading to changes in cellular state that can in turn feed back on global RNA production and turnover. Total RNA profiling of gene expression upon Myc regulation in two different cell types by Illumina sequencing

2014-07-07 | E-GEOD-51008 | biostudies-arrayexpress

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