Epigenome-wide association analysis of pancreatic exocrine cells from high-fat- and normal diet-fed mice and its potential use for understanding the oncogenesis of human pancreatic cancer
Epigenome-wide association analysis of pancreatic exocrine cells from high-fat- and normal diet-fed mice and its potential use for understanding the oncogenesis of human pancreatic cancer
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DOI：
10.1016/j.bbrc.2022.10.105
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发表时间：
2022-11-11
影响因子：
3.1
通讯作者：
Miwa，Naofumi
中科院分区：
文献类型：
--
作者：
Araki，Tomoyuki;Nagashima，Masaru;Miwa，Naofumi
异常DNA甲基化与包括胰腺癌（PC）在内的多种人类癌症的肿瘤发生相关。PC是第七大常见癌症，肥胖是已知的高风险因素。然而，肥胖是否会影响胰腺外分泌细胞的DNA甲基化，以及这是否会影响PC的发育仍不清楚。在此，我们对从高脂饮食诱导的肥胖（DIO）小鼠中分离的胰腺外分泌细胞进行了全表观基因组分析。使用Illumina小鼠甲基化BeadChip阵列（280 K），我们鉴定了316个差异甲基化区域（DMR），这些区域富集了细胞过程，如DNA修复，转录调节和细胞增殖，这证实了DIO小鼠胰腺细胞中某些代谢过程的肥胖相关失调。将DMR与IB PC阶段的DMR进行比较有助于确定82个重叠的DMR。DIO小鼠和IB期PC的胰腺外分泌细胞共有三条途径，包括涉及PLC、PKC、SMAD 2/3和TRKA的细胞肥大途径，涉及CREA和AMPK的代谢控制途径，以及涉及K+通道的钾调节途径。与DIO小鼠相比，在PC中观察到甲基化水平的增强改变。这些发现表明肥胖影响DIO小鼠胰腺外分泌细胞的DNA甲基化，并且肥胖个体中DNA甲基化的持续失调可能导致PC的发展。
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 involvingPLC,PKC,SMAD2/3, andTRKA; the metabolic control pathway involvingCREBand 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.