RESUMO
Aberrant DNA methylation is associated with oncogenesis of various human cancers, including pancreatic cancer (PC). PC is the seventh most common cancer, and obesity is a known high-risk factor. However, whether obesity influences DNA methylation in pancreatic exocrine cells and if this influences PC development remain unclear. Here, we performed an epigenome-wide analysis of isolated pancreatic exocrine cells obtained from mice with high-fat-diet-induced obesity (DIO). Using the Illumina Mouse Methylation BeadChip array (280K), we identified 316 differentially methylated regions (DMRs) that were enriched for cellular processes, such as DNA repair, transcription regulation, and cell proliferation, which confirmed obesity-related dysregulation of certain metabolic processes in the pancreatic cells in DIO mice. Comparing the DMRs with those in stage IB PC helped identify 82 overlapping DMRs. Three pathways including the cell hypertrophy pathway involving PLC, PKC, SMAD2/3, and TRKA; the metabolic control pathway involving CREB and AMPK; and the potassium regulation pathway involving K+-channels, were shared between the pancreatic exocrine cells from DIO mice and stage IB PC. Enhanced alteration in the methylation level was observed in PC compared to that in DIO mice. These findings indicated that obesity influences DNA methylation in pancreatic exocrine cells of DIO mice, and persistent dysregulation of DNA methylation in individuals with obesity may result in PC development.
Assuntos
Epigenoma , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Metilação de DNA , Dieta Hiperlipídica/efeitos adversos , Obesidade/complicações , Obesidade/genética , Camundongos Obesos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/complicações , Carcinogênese/genética , Transformação Celular Neoplásica/genética , Epigênese Genética , Neoplasias PancreáticasRESUMO
Astrocytes play active roles in the regulation of synaptic transmission. Neuronal excitation can evoke Ca(2+) transients in astrocytes, and these Ca(2+) transients can modulate neuronal excitability. Although only a subset of astrocytes appears to communicate with neurons, the types of astrocytes that can regulate neuronal excitability are poorly characterized. We found that â¼30% of astrocytes in the brain express transient receptor potential vanilloid 4 (TRPV4), indicating that astrocytic subtypes can be classified on the basis of their expression patterns. When TRPV4(+) astrocytes are activated by ligands such as arachidonic acid, the activation propagates to neighboring astrocytes through gap junctions and by ATP release from the TRPV4(+) astrocytes. After activation, both TRPV4(+) and TRPV4(-) astrocytes release glutamate, which acts as an excitatory gliotransmitter to increase synaptic transmission through type 1 metabotropic glutamate receptor (mGluR). Our results indicate that TRPV4(+) astrocytes constitute a novel subtype of the population and are solely responsible for initiating excitatory gliotransmitter release to enhance synaptic transmission. We propose that TRPV4(+) astrocytes form a core of excitatory glial assembly in the brain and function to efficiently increase neuronal excitation in response to endogenous TRPV4 ligands.