CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms
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ABSTRACT:
PROVIDER: PRJNA558145 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Exon Level Expression Profiling of HeLa cells depleted of DNMT1 by 2 independent siRNAs In HeLa cells where depletion of DNMT1 was sufficient to cause reduced levels of DNA methylation inside the body of CD44 and reduced usage of CD44 variant exons, without affecting splicing factors regulating CD44.
2021-05-10 | GSE135277 | GEO
Project description:DNA methylation (meDNA) is a modulator of alternative splicing, and splicing perturbations are involved in tumorigenesis nearly as frequently as DNA mutations. However, the impact of meDNA on tumorigenesis via splicing-mediated mechanisms has not been thoroughly explored. Here, we found that HCT116 colon carcinoma cells inactivated for the DNA methylases DNMT1/3b undergo a partial epithelial to mesenchymal transition associated with increased CD44 variant exon skipping. These skipping events are directly mediated by the loss of intragenic meDNA and the chromatin factors MBD1/2/3 and HP1γ and are also linked to phosphorylation changes in elongating RNA polymerase II. The role of meDNA in alternative splicing was confirmed by using the dCas9/DNMT3b tool. We further tested whether the meDNA level could have predictive value in the MCF10A model for breast cancer progression and in patients with acute lymphoblastic leukemia (B ALL). We found that a small number of differentially spliced genes, mostly involved in splicing and signal transduction, are correlated with the local modulation of meDNA. Our observations suggest that, although DNA methylation has multiple avenues to affect alternative splicing, its indirect effect may also be mediated through alternative splicing isoforms of these meDNA sensors.
| S-EPMC8216461 | biostudies-literature
Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional translation. Purified ribosomes interact with and stimulate recombinant cGAS catalytic activity in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and cause the re-localization of cGAS from the nucleus to the cytosol. Other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.
2020-05-26 | GSE151127 | GEO
Project description:The cGAS-STING pathway, a central component of the innate immune system, senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to mediate inflammation. Here we report the unexpected discovery that cGAS senses dysfunctional protein production. Purified ribosomes interact with and stimulate the catalytic activity of recombinant cGAS in vitro. Disruption of the ribosome-associated protein quality control pathway, which detects and resolves ribosome collisions, results in cGAS- and STING-dependent ISG expression, and causes the re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and other orthogonal perturbations that lead to elevated levels of collided ribosomes cause re-localization of cGAS as well. Thus, the cGAS-STING pathway senses and responds to translation stress. These findings have implications for the inflammatory responses to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.
2021-09-09 | PXD019359 | Pride
Project description:Sus scrofa CD44, CD44 molecule [Source:VGNC Symbol;Acc:VGNC:99614], is expressed in 8 baseline experiment(s);
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Project description:Macaca mulatta CD44, CD44 molecule [Source:VGNC Symbol;Acc:VGNC:100905], is expressed in 3 baseline experiment(s);
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Project description:Sus scrofa CD44, CD44 molecule [Source:VGNC Symbol;Acc:VGNC:99614], is differentially expressed in 4 experiment(s);
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Project description:Macaca mulatta CD44, CD44 molecule [Source:VGNC Symbol;Acc:VGNC:100905], is differentially expressed in 1 experiment(s);
| ENSMMUG00000004327 | ExpressionAtlas
Project description:Mus musculus Cd44, CD44 antigen [Source:MGI Symbol;Acc:MGI:88338], is differentially expressed in 188 experiment(s);
| ENSMUSG00000005087 | ExpressionAtlas
Project description:Mus musculus Cd44, CD44 antigen [Source:MGI Symbol;Acc:MGI:88338], is expressed in 40 baseline experiment(s);
| ENSMUSG00000005087 | ExpressionAtlas