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DNA methylation memory of acinar-ductal transition state altering Kras-downstream Pi3k and Rho GTPase signaling

ABSTRACT: DNA methylation memory of acinar-ductal transition state altering Kras-downstream Pi3k and Rho GTPase signaling

PROVIDER: PRJNA1047540 | ENA |

REPOSITORIES: ENA

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DNA methylation memory of acinar-ductal transition state altering Kras-downstream Pi3k and Rho GTPase signaling [WGBS]

Project description:A critical area of recent cancer research is the emergence of transition states between normal and cancer that exhibit increased cell plasticity which underlies tumor cell heterogeneity. Pancreatic ductal adenocarcinoma (PDAC) arises from a transition state termed acinar-to-ductal metaplasia (ADM), in which digestive enzyme-producing acinar cells acquire a transient ductal epithelium-like phenotype while maintaining their geographical acinar organization. ADM is created by overexpression of the Kruppel-like factor 4 gene (KLF4) in the absence of oncogenic driver mutations. Here, we investigate the DNA methylation landscape and corresponding transcriptional landscape of the mutation-free ADM transition state and the subsequent reversion to a normal acinar phenotype. We ask to what extent cells retain a memory of the ADM transition state via DNA methylation, examine potential regulators of altered DNA methylation during ADM, and investigate the relationship of the ADM transition state to human pancreatic cancer precursor lesions. These findings may inform the mechanisms not only of heritable epigenetic memory of transition states and inflammation, but also of how epigenetic alterations presage or even elicit genetic mutations in cancer.

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DNA methylation memory of acinar-ductal transition state altering Kras-downstream Pi3k and Rho GTPase signaling [spatial transcriptomics]

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DNA methylation memory of acinar-ductal transition state altering Kras-downstream Pi3k and Rho GTPase signaling

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2025-03-10 | GSE249143 | GEO

Transcriptional regulation by the novel Rho GTPase RhoBTB2.

Project description:RhoBTB2 is a novel Rho GTPase that undergoes loss, underexpression and mutation in breast and lung cancer. We have shown that we can mimic loss of RhoBTB2 through siRNA treatment of primary cells. We propose to perform comparative microarray analysis of primary lung cells to establish the identification of the gene targets of RhoBTb2 regulation. Keywords: Effects of siRNA expression

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YAP controls cell migration and invasion through a Rho-GTPase switch

Project description:Delineating the mechanisms controlling the invasive spread of non-diseased and transformed cells is central to understanding diverse processes including cancer progression. Here, we found that Yes-associated protein (YAP), a central transcriptional regulator implicated in controlling organ and body size, modulated a Rho-GTPase switch that drives cellular migration by transactivating the Rac1-GEF protein TRIO through direct modulation of its intronic enhancer. Additionally, YAP and TRIO may promote invasive behavior through putative crosstalk with STAT3 signaling, a potential downstream target. Although we found this YAP-dependent infiltrative program in many cell types, it was particularly enhanced in a patient-specific manner in the most common malignant brain tumor, glioblastoma (GBM), where hyperactivation of the YAP, TRIO, and STAT3 signatures also conferred poor clinical outcome. Our analysis suggests that the YAP-TRIO-Rho-GTPase signaling network identified in this study is a ubiquitous regulator of invasive cell spread in both physiological and pathological contexts. In this dataset, we knocked down YAP in two patient-derived GBM primary cell lines (JHGB612 and JHGB651) and performed microarray analysis.

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Multi-Omics Integration Implicates Rac/Rho GTPase Cycling in Vascular Cognitive Impairment and Dementia Pathogenesis

Project description:Background: Vascular cognitive impairment and dementia (VCID) represents a spectrum of cognitive disorders linked to cerebrovascular pathology, yet its molecular underpinnings remain misunderstood. Methods: We conducted a multi-omics analysis of post-mortem brain tissue from the superior parietal lobe (Brodmann area 7) in 19 individuals with neuropathologically confirmed VCID and 21 age-matched controls. Whole genome sequencing, genome-wide DNA methylation profiling, transcriptomic analysis, and metabolomics profiling were performed to identify molecular signatures and integrated pathways involved in VCID pathogenesis. Results: Epigenome-wide association analysis revealed widespread hypermethylation in VCID, with significant enrichment of genes involved in the Rac/Rho GTPase cycle and cytoskeletal remodeling. Transcriptomic analysis confirmed dysregulation of small GTPase signaling, oxidative stress responses, and lipid metabolism. Metabolomic profiling identified altered levels of diacylglycerols (DAGs) and phosphatidylethanolamines (PEs), which showed strengthened associations with Rac/Rho pathway genes in VCID compared to controls. Conclusions: Our integrative multi-omics study identifies the Rac/Rho GTPase cycle as a convergent pathway disrupted at the genomic, epigenomic, transcriptomic, and metabolic levels in VCID. Lipid metabolism, particularly involving DAGs and PEs, emerged as a key downstream effector contributing to VCID. These findings offer mechanistic insights into VCID pathogenesis and suggest lipid signaling pathways as promising therapeutic targets for intervention.

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TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing

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TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing

Project description:TRIM67 drives tumorigenesis in oligodendrogliomas through Rho GTPase-dependent membrane blebbing

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YAP controls cell migration and invasion through a Rho-GTPase switch

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