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Inactivation of the exosome ribonuclease DIS3 triggers the pluripotency factor LIN28B, repressing let-7 miRNAs and unleashing MYC and RAS.

ABSTRACT: Somatic mutations affecting DIS3, the catalytic component of the RNA exosome, have been found in up to 18% of patients affected by the hematological cancer multiple myeloma. Here we show that DIS3 targets and degrades the pluripotency factor LIN28B. In cancer cells, DIS3 inactivation leads to enhanced LIN28B expression, thus disrupting the let-7 miRNAs tumor suppressor network and ultimately increasing protein levels of crucial oncogenes such as MYC and RAS. DIS3 represents the catalytic component of the exosome. The exosome is required for cell viability and targets several RNA species, including pre-mRNAs, pre-tRNAs, pre-rRNAs, snRNAs and snoRNAs. To gain insight on the macular wiring underlying DIS3 activity in mammalian cells, we comprehensively evaluated expression profiles, including miRNAs, in various cell lines, upon DIS3 knockdown.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE55246 | GEO | 2015/06/12

SECONDARY ACCESSION(S): PRJNA238992

REPOSITORIES: GEO

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Inactivation of the exosome ribonuclease DIS3 triggers the pluripotency factor LIN28B, repressing let-7 miRNAs and unleashing MYC and RAS.

Project description:Somatic mutations affecting DIS3, the catalytic component of the RNA exosome, have been found in up to 18% of patients affected by the hematological cancer multiple myeloma. Here we show that DIS3 targets and degrades the pluripotency factor LIN28B. In cancer cells, DIS3 inactivation leads to enhanced LIN28B expression, thus disrupting the let-7 miRNAs tumor suppressor network and ultimately increasing protein levels of crucial oncogenes such as MYC and RAS. DIS3 represents the catalytic component of the exosome. The exosome is required for cell viability and targets several RNA species, including pre-mRNAs, pre-tRNAs, pre-rRNAs, snRNAs and snoRNAs. To gain insight on the macular wiring underlying DIS3 activity in mammalian cells, we comprehensively evaluated expression profiles, including miRNAs, in various cell lines, upon DIS3 knockdown. This series of microarray experiments contains the miRNA expression profiles of independent replicates of RPMI-8226, KMS12-BM multiple myeloma cell lines and HEK-293T cells, knocked-down with a scrambled or hDIS3 sh4 and collected 72 hours after infection. 500 nanograms of total RNA were processed using the FlashTag labeling kit, which uses a tailing reaction followed by ligation of the biotinylated signal molecule to the target RNA sample. The labelled RNA was then hybridized to Affymetrix GeneChip® microRNA arrays v1.0, following the Affymetrix manufacturer's instructions.

2015-06-12 | E-GEOD-55246 | biostudies-arrayexpress

DIS3 ribonuclease degrades Pou6f1 to promote mouse pre-implantation cell differentiation

Project description:Mammalian early embryonic development involves precisely regulated cell differentiation. Discovering new regulators and profiling their crosstalk have been extensively studied and remain open questions. To identify novel developmental repressors, we established the knockout mouse model of Dis3, an RNA exosome associated RNase. Homozygous Dis3 null embryos have morula-to-blastocyst transition arrest and they lack cell differentiation. By single embryo RNA-seq, we identified Pou6f1 accumulation by DIS3 depletion. Sustained POU6F1 binds and represses the transcription of Nanog and Cdx2. In addition, a broader role of POU6F1 in cell fate transition is also revealed from derived mouse embryonic stem cells. We also tested DIS3 mutations and discovered their effects in causing cell transformation. Our findings uncover a new regulatory pathway of DIS3-POU6F1 in regulating pre-implantation cell differentiation in early mammalian embryogenesis.

2022-04-28 | GSE201218 | GEO

Human DIS3 shapes the RNA polymerase II transcriptome degrading variety of unwanted transcripts.

Project description:Human DIS3 is a nuclear, catalytic subunit of the exosome complex containing exonucleolytic and endonucleolytic active domains. To identify DIS3 targets genome-wide we conducted comprehensive transcriptomic analysis of HEK293 cells producing mutated DIS3 versions and Photoactivatable Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) experiments. Pervasive transcription products like Promoter Upstream Transcripts (PROMPTs) accumulated robustly in catalytic DIS3 mutants, representing ~8% of PAR-CLIP reads. Importantly, RNAs originating from unannotated genomic regions increased ~2.5 times in double DIS3 mutants, covering ~70% of genome and allowing for discovery of thousands of novel transcripts. The first intron of many pre-mRNAs accumulated in DIS3 mutants indicating a widespread premature RNA polymerase II termination. The short form of NEAT1 lincRNA was overexpressed in DIS3 mutants, leading to increased number of paraspeckles. Moreover, there was a global deregulation of mRNAs in DIS3 double mutant. Finally, snoRNA precursors accumulated, which correlated with a strong PAR-CLIP signal indicating that DIS3 but not RRP6 is a main snoRNA processing enzyme. In aggregate, we demonstrate that DIS3 is a major nucleoplasmic activity responsible for shaping the human transcriptome.

2015-08-20 | GSE64332 | GEO

Pronounced and Extensive Microtubule Defects in a Saccharomyces cerevisiae DIS3 Mutant

Project description:The recently proposed exozyme hypothesis posits that subunits of the RNA processing exosome assemble into structurally distinct protein complexes that function in disparate cellular compartments and RNA metabolic pathways. Here, in a genetic test of this hypothesis, we examine the role of Dis3 -- an essential polypeptide with endo- and 3' to 5' exo-ribonuclease activity -- in cell cycle progression. We present several lines of evidence that perturbation of DIS3 affects microtubule (MT) localization and structure in Saccharomyces cerevisiae. Cells with a DIS3 mutation: (i) accumulate anaphase and pre-anaphase mitotic spindles; (ii) exhibit spindles that are mis-oriented and displaced from the bud neck; (iii) harbor elongated spindle-associated astral MTs; (iv) have an increased G1 astral MT length and number; and (v) are hypersensitive to MT poisons. Mutations in the core exosome genes RRP4 and MTR3 and the exosome cofactor gene MTR4 -- but not other exosome subunit gene mutants -- also elicit MT phenotypes. RNA deep sequencing analysis (RNA-seq) shows broad changes in the levels of cell cycle- and microtubule-related transcripts in mutant strains. Collectively, the different mitotic phenotypes and distinct sets of mRNAs affected by the exosome subunit and cofactor mutants studied here suggest that Dis3 has a core exosome-independent role(s) in cell cycle progression. These observations are consistent with the predictions of the exozyme hypothesis and also suggest an evolutionarily conserved role for Dis3 in linking RNA metabolism, MTs, and mitotic progression. RNA-seq analysis of total RNA harvested from WT, mtr3-1, mtr4-1, and Dis3^mtr (rrp44-1/mtr17-1) Saccharomyces cerevisiae strains after a temperature shift.

2013-01-01 | E-GEOD-29018 | biostudies-arrayexpress

Pronounced and Extensive Microtubule Defects in a Saccharomyces cerevisiae DIS3 Mutant

2013-01-01 | GSE29018 | GEO

DIS3 ribonuclease is required for the maintenance of spermatogenic lineage in mice

Project description:Spermatogonial stem cells (SSCs) self-renewal and differentiation are the foundation for continious spermatognenesis in mice. Here, we investigate the essential role of DIS3 in maintaining SSC homeostasis and facilitating germ cell differentiation to ensure male fertility. Conditional inactivation of DIS3 in male germ cells have severely impaired SSC self-renewal and differentiation, which results in the failure of spermatogenesis associated with a Sertoli cell-only syndrome and adult sterility. RNA-seq analysis reveales that Dis3 deficiency abolishes its nucleolytic activity and causes significant dysregulation of the expression of transcripts in Dis3 mutant testes. We have also found that the pervasive transcription products described previously, such as Promoter Upstream Transcripts (PROMPTs), accumulate robustly upon DIS3 dysfunction in Dis3 cKO testes. In addition, scRNA-seq analysis indicates that DIS3 mutation significantly impairs germline stem cell development that blocks stem cell proliferation and differentiation. Overall, we show that DIS3 ribonuclease plays a critical role in the maintenance of spermatogenic lineage during spermatogenesis in mice.

2020-08-20 | GSE156505 | GEO

RNA accumulation profiles generated by RNA-Seq in mutants of Schizosaccharomyces pombe exosome exonucleases Rrp6 and Dis3

Project description:We studied the differences in RNA accumulation profiles of an rrp6-null mutant and compared it to RNA accumulation in rrp6 catalytic mutants as well as dis3 mutants using RNA-Seq. Rrp6 and Dis3 are exosome exoncleases, therefore this study was used to determine their target RNAs We examined 3' end RNA processing changes by RNA-Seq in wild type, rrp6Δ and rrp6-cat mutants. Libraries were made by 3' adapter ligation

2015-12-01 | GSE74411 | GEO

Global analysis of the nuclear processing of unspliced U12-type introns by the exosome

Project description:we analyzed globally the effect of exosome processing on the nuclear pre-mRNA transcripts by inactivating either the RRP41 or DIS3 subunit of the exosome. Using SOLiD RNA sequencing technology, we report 30-120 million mapped cellular compartment specific reads per sample allowing the detection of unspliced pre-mRNAs. We show that RRP41 and DIS3 knockdowns stabilize an overlapping set of U12-type introns. Studying the global effect of the exosome (Rrp41 or Dis3 subunit) knockdown comparing to the control sample.

2014-05-26 | E-GEOD-52539 | biostudies-arrayexpress

DIS3 ribonuclease degrades Pou6f1 to promote mouse pre-implantation cell differentiation

Project description:DIS3 ribonuclease degrades Pou6f1 to promote mouse pre-implantation cell differentiation

| PRJNA830446 | ENA

The ribonuclease DIS3 promotes let-7 miRNA maturation by degrading the pluripotency factor LIN28B mRNA.

Project description:Multiple myeloma, the second most frequent hematologic tumor after lymphomas, is an incurable cancer. Recent sequencing efforts have identified the ribonuclease DIS3 as one of the most frequently mutated genes in this disease. DIS3 represents the catalytic subunit of the exosome, a macromolecular complex central to the processing, maturation and surveillance of various RNAs. miRNAs are an evolutionarily conserved class of small noncoding RNAs, regulating gene expression at post-transcriptional level. Ribonucleases, including Drosha, Dicer and XRN2, are involved in the processing and stability of miRNAs. However, the role of DIS3 on the regulation of miRNAs remains largely unknown. Here we found that DIS3 regulates the levels of the tumor suppressor let-7 miRNAs without affecting other miRNA families. DIS3 facilitates the maturation of let-7 miRNAs by reducing in the cytoplasm the RNA stability of the pluripotency factor LIN28B, a inhibitor of let-7 processing. DIS3 inactivation, through the increase of LIN28B and the reduction of mature let-7, enhances the translation of let-7 targets such as MYC and RAS leading to enhanced tumorigenesis. Our study establishes that the ribonuclease DIS3, targeting LIN28B, sustains the maturation of let-7 miRNAs and suggests the increased translation of critical oncogenes as one of the biological outcomes of DIS3 inactivation.

| S-EPMC4446438 | biostudies-literature

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