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CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms

ABSTRACT: CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms

PROVIDER: PRJNA558145 | ENA |

REPOSITORIES: ENA

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CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms

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

CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms.

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

cGAS Senses Translation Stress Through Direct Binding to Ribosomes

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

cGAS Senses Translation Stress Through Direct Binding to Ribosomes

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

Intragenic DNA inversions expand bacterial coding capacity

Project description:Bacteria can generate heterogeneity through phase variation, including enzyme-mediated inversion of specific intergenic regions of genomic DNA. We developed a computation tool that identifies invertible elements using long-read datasets, PhaVa. We identified over 300 ‘intragenic invertons,’ a new class of invertible elements entirely within genes, in both bacteria and archaea. In the gut commensal Bacteroides thetaiotaomicron, we experimentally characterized an intragenic inverton in the thiamine biosynthesis protein thiC. We used mass spectrometry in data-independent acquisition mode to identify and quantify B. theta proteins, including thiC inverton expression at the protein level.

2024-08-06 | PXD054577 | Pride

cGAS Senses Translation Stress Through Direct Binding to Ribosomes

Project description:cGAS Senses Translation Stress Through Direct Binding to Ribosomes

| PRJNA634841 | ENA

Direct and indirect effects of a social supergene

Project description:Direct and indirect effects of a social supergene

| PRJNA847170 | ENA

Evaluation of gene expression between CD44+ and CD44- cells in colonospheres

Project description:To identify genes that are differentially expressed between CD44+ and CD44- cells in colonospheres, we have employed whole genome microarray expression profiling as a discovery platform. Colonospheres from four colon cancer patients were sorted into CD44+ and CD44- cells using the FACS Aria II Cell Sorter, and total RNA extracted from the cells were labeled with Cy3 and used for microarray analyses with Agilent Whole Human Genome Oligo Microarrays. Gene expression in fluorescence-activated cell-sorted CD44+ and CD44- cells derived from four colon cancer patients was measured.

2012-12-07 | E-GEOD-38706 | biostudies-arrayexpress

Gene expression profiles in CD44- and CD44+ hepatocellular carcinoma HuH7 cells

Project description:To investigate the significance of CD44+ hepatocellular carcinoma (HCC) HuH7 cells, gene expression profiles of CD44-positive HuH7, CD44-negative HuH7, and human nomal hepatocyes were analyzed. Results provide the insight into the significance of CD44-positive HCC cells as the liver CSCs.

2016-09-01 | GSE84223 | GEO

microRNA expression profiles in CD44- and CD44+ hepatocellular carcinoma HuH7 cells

Project description:To investigate the significance of CD44+ hepatocellular carcinoma (HCC) HuH7 cells, microRNA (miRNA) expression profiles of CD44-positive HuH7, CD44-negative HuH7, and human nomal hepatocyes were analyzed. Results provide the insight into the significance of CD44-positive HCC cells as the liver CSCs.

2016-09-01 | GSE84224 | GEO

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