Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1124425 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29425470.fastq.gz | Fastqsanger.gz | |||
| SRR29425471.fastq.gz | Fastqsanger.gz | |||
| SRR29425472.fastq.gz | Fastqsanger.gz |
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Project description:Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited. However, the mechanisms underlying cGAS recruitment to chromatin and the functions of chromatin-bound cGAS (ccGAS) remain unclear. Here, we demonstrate that mTORC2-mediated serine 37 phosphorylation promotes human cGAS chromatin localization, regulating colorectal cancer cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions to regulate expression of genes involved in glutaminolysis and DNA replication. Knockdown of ccGAS inhibits colorectal cancer cell growth but induces chemoresistance under fluorouracil exposure both in vitro and in vivo. Moreover, inhibition of kidney-type glutaminase (KGA), a downstream target of ccGAS, overcomes chemoresistance induced by ccGAS knockdown in human and murine colorectal cancer. Thus, our study demonstrates that ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning, and illustrates that simultaneously targeting mTORC2-ccGAS and KGA provides a promising theraputic strategy to eliminate quiescent resistant cancer cells.
2025-05-07 | PXD053068 | Pride
Project description:Despite extensive genetic heterogeneity, lung tumors frequently converge on shared signaling dependencies that remain therapeutically underexploited. Here, we identify mTORC2 signaling as a convergent dependency across genetically distinct lung cancer subtypes and demonstrate that RICTOR-dependent mTORC2 activity promotes tumor progression through HIF-1β-dependent sphingolipid reprogramming. Elevated mTORC2 signaling in lung adenocarcinoma was associated with poor overall survival, metastatic dissemination and metabolic rewiring. Using complementary genetically engineered mouse models of Rictor deletion or overexpression in Kras-driven lung tumors, we show that mTORC2 activity is dispensable for normal lung homeostasis but required for tumor progression and metabolic adaptation in vivo. Mechanistically, mTORC2 stabilized HIF-1β by preventing its ubiquitin-independent proteasomal degradation through a non-canonical PKCα-CK2 signaling axis, independently of AKT. Integrated multi-omics analyses revealed that mTORC2-HIF-1β signaling drives extensive sphingolipid remodeling through the regulation of key metabolic enzymes, including SPHK1 and SPTLC2. Accordingly, pharmacological inhibition of sphingolipid metabolism markedly impaired the growth of mTORC2-driven lung tumors in vivo. Together, our findings uncover a previously unrecognized mTORC2-HIF-1β-sphingolipid signaling axis that creates targetable metabolic vulnerabilities in lung cancer.
2026-07-01 | GSE336140 | GEO
Project description:Despite extensive genetic heterogeneity, lung tumors frequently converge on shared signaling dependencies that remain therapeutically underexploited. Here, we identify mTORC2 signaling as a convergent dependency across genetically distinct lung cancer subtypes and demonstrate that RICTOR-dependent mTORC2 activity promotes tumor progression through HIF-1β-dependent sphingolipid reprogramming. Elevated mTORC2 signaling in lung adenocarcinoma was associated with poor overall survival, metastatic dissemination and metabolic rewiring. Using complementary genetically engineered mouse models of Rictor deletion or overexpression in Kras-driven lung tumors, we show that mTORC2 activity is dispensable for normal lung homeostasis but required for tumor progression and metabolic adaptation in vivo. Mechanistically, mTORC2 stabilized HIF-1β by preventing its ubiquitin-independent proteasomal degradation through a non-canonical PKCα-CK2 signaling axis, independently of AKT. Integrated multi-omics analyses revealed that mTORC2-HIF-1β signaling drives extensive sphingolipid remodeling through the regulation of key metabolic enzymes, including SPHK1 and SPTLC2. Accordingly, pharmacological inhibition of sphingolipid metabolism markedly impaired the growth of mTORC2-driven lung tumors in vivo. Together, our findings uncover a previously unrecognized mTORC2-HIF-1β-sphingolipid signaling axis that creates targetable metabolic vulnerabilities in lung cancer.
2026-07-01 | GSE336137 | GEO
Project description:We herein demonstrate that mammalian target of rapamycin complex 2 (mTORC2), a critical core component of the growth factor signaling system, globally alters histone acetylation through metabolic reprogramming in the highly malignant brain tumor glioblastoma (GBM). Integrated analyses unravel that mTORC2 regulates iron trafficking via histone H3K9 acetylation of the ferritin promoter, facilitating GBM growth and survival. These findings nominate mTORC2 as a critical epigenetic regulator of iron metabolism in cancer.
2019-11-07 | GSE133117 | GEO
Project description:cGAS is a cytosolic DNA sensor essential for host defense against viral/bacterial infections. To prevent misactivation, nuclear cGAS is suppressed through nucleosome tethering or BAF binding. However, pathophysiological functions of nuclear cGAS beyond its role as an inactive enzyme remain unclear. We mapped the genome-wide cGAS localization and identify its association with AP-1 transcription factors through a novel TAD domain, operating independently of its established nucleosome binding or DNA binding ability. We demonstrated cGAS regulated LGALS3 transcription and expression, through inhibiting ACAA2 activity, reduced fatty acid oxidation and acetyl-CoA production, thereby lowering cholesterol levels. cGAS depletion increased cellular cholesterol to activate mTORC2/Akt signaling. This leads to increased cell size, enhanced tumor growth and resistance chemotherapy. Together, our study uncovers a novel nuclear cGAS function in governing transcriptome to link cell metabolism with tumor growth and therapy resistance.
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Project description:<p>Epigenetic alterations are central drivers of cardiovascular aging, with histone modifications regulating gene expression through chromatin remodeling and changes in DNA accessibility. However, the mechanisms underlying these epigenetic shifts in the aging heart remain poorly defined. Here, we identify an age-associated accumulation of the repressive histone mark H3K27me3 in the myocardium of mice and humans, implicating this modification in myocardial aging. Elevated H3K27me3 was associated with impaired glutamine metabolism, driven by reduced expression of the amino acid transporter SLC1A5. Clinically, low circulating glutamine levels correlated with increased heart failure incidence, and genetic variants in SLC1A5 were linked to heightened cardiovascular disease risk. Mechanistically, elevated myocardial H3K27me3 suppressed cardiomyocyte autophagy and induced metabolic reprogramming, thereby promoting age-related myocardial dysfunction. Dietary glutamine supplementation in aged mice reduced H3K27me3 accumulation and improved myocardial function. Collectively, these findings identify a novel epigenetic mechanism underlying cardiac aging and highlight the glutamine–SLC1A5 axis as a potential therapeutic target for preserving myocardial function with age.</p>
2026-02-11 | MTBLS13890 | MetaboLights
Project description:Cisplatin resistance in bladder cancer (BCa) is driven by metabolic reprogramming that enhances glycolysis and lactate production. Here, we report that lactate-induced histone H3K18 lactylation (H3K18la) drives chemoresistance by activating a novel signaling axis that couples epigenetic regulation with mitochondrial quality control. Through integrative multi-omics analysis, we identified HNRNPF as a key effector downstream of H3K18la, with its promoter being directly enriched by H3K18la in cisplatin-resistant BCa cells. Unexpectedly, HNRNPF, primarily known as an RNA-binding protein, promotes chemoresistance through a non-canonical mechanism: it directly interacts with the core mitophagy protein Parkin. Mechanistically, the RRM2 domain of HNRNPF binds the R0 domain of Parkin, facilitating Parkin’s recruitment to damaged mitochondria. This interaction potentiates Parkin’s E3 ubiquitin ligase activity, leading to enhanced ubiquitination of VDAC1 and robust activation of mitophagy. Collectively, our findings establish the H3K18la-HNRNPF-Parkin axis as a previously unrecognized signaling cascade that bridges epigenetic reprogramming with to mitochondrial quality control in chemoresistance. Targeting this axis, particularly the HNRNPF-Parkin interaction or mitophagy activation, may represent a novel therapeutic strategy to overcome cisplatin resistance in BCa, pending further validation in preclinical models.
2026-03-30 | GSE325983 | GEO
Project description:mTOR complex 2 (mTORC2) phosphorylates AKT in a hydrophobic motif site that is a biomarker of insulin sensitivity. In adipocytes, mTORC2 regulates glucose and lipid metabolism; however, the mechanism has been unclear because downstream AKT signaling appears unaffected by mTORC2 loss. Here, by applying immunoblotting, targeted phosphoproteomics and metabolite profiling in brown preadipocytes, we identify ATP-citrate lyase (ACLY) as a distinctly mTORC2-sensitive AKT substrate. mTORC2 appears dispensable for most other AKT actions examined indicating a previously unappreciated selectivity in mTORC2-AKT signaling. Rescue experiments show brown preadipocytes require the mTORC2/AKT/ACLY pathway to induce PPAR-gamma and establish the epigenetic landscape during differentiation. mTORC2 also acts through ACLY in mature brown adipocytes to increase ChREBP activity, histone acetylation, and gluco-lipogenic gene expression. Substrate utilization studies additionally implicate mTORC2 in promoting acetyl-CoA synthesis from acetate through acetyl-CoA synthetase 2 (ACSS2). These data suggest that a principal mTORC2 action is controlling nuclear-cytoplasmic acetyl-CoA synthesis.
| MSV000084309 | MassIVE
Project description:Epithelial to mesenchymal transition (EMT) is an extreme example of cell plasticity, important for normal development, injury repair, and malignant progression. Widespread epigenetic reprogramming occurs during stem cell differentiation and malignant transformation, but EMT-related epigenetic reprogramming is poorly understood. Here we investigated epigenetic modifications during TGF-β-mediated EMT. While DNA methylation was unchanged during EMT, we found global reduction of the heterochromatin mark H3-lys9 dimethylation (H3K9Me2), increase of the euchromatin mark H3-lys4 trimethylation (H3K4Me3), and increase of the transcriptional mark H3-lys36 trimethylation (H3K36Me3). These changes were largely dependent on lysine-specific deaminase-1 (LSD1), and LSD1 loss-of-function experiments showed marked effects on EMT-driven cell migration and chemoresistance. Genome-scale mapping revealed that chromatin changes were largely specific to large organized heterochromatin K9-modifications (LOCKs), suggesting that EMT is characterized by reprogramming of specific chromatin domains across the genome.
2011-07-03 | GSE28291 | GEO
Project description:Despite rapid progress in characterizing transcription factor-driven reprogramming of somatic cells to an induced pluripotent stem (iPS) cell state, many mechanistic questions still remain. To gain insight into the earliest events in the reprogramming process, we systematically analyzed the transcriptional and epigenetic changes that occur during early factor induction after discrete numbers of divisions. We observed rapid, genome-wide changes in the euchromatic histone modification, H3K4me2, at more than a thousand loci including large subsets of pluripotency or developmentally related gene promoters and enhancers. In contrast, patterns of the repressive H3K27me3 modification remained largely unchanged except for focused depletion specifically at positions where H3K4 methylation is gained. These chromatin regulatory events precede transcriptional changes within the corresponding loci. Our data provide evidence for an early, organized, and population-wide epigenetic response to ectopic reprogramming factors that clarify the temporal order through which somatic identity is reset during reprogramming. Gene expression was measured by Affymetric microarrays during the initial phase of the reprogramming of mouse embryonic fibroblasts.
2011-01-03 | E-GEOD-26096 | biostudies-arrayexpress