肝细胞癌中的硅CPG甲基化分析鉴定了与基因表达断开的组织和肿瘤类型特异性标记
Comprehensive in silico CpG methylation analysis in hepatocellular carcinoma identifies tissue- and tumor-type specific marks disconnected from gene expression
影响因子:4.30000
分区:生物学3区 / 生化与分子生物学3区 生理学3区
发表日期:2024 Nov
作者:
Idoia Bilbao, Miriam Recalde, Fabrice Daian, José Maria Herranz, María Elizalde, Mercedes Iñarrairaegui, Matteo Canale, Maite G Fernández-Barrena, Andrea Casadei-Gardini, Bruno Sangro, Matías A Ávila, Manuel F Landecho Acha, Carmen Berasain, María Arechederra
摘要
DNA甲基化对染色质结构，转录调节和基因组稳定性至关重要，从而定义了细胞身份。富含CpG的区域的异常高甲基化在癌症中很常见，影响基因表达。然而，仍在研究中，个人表观遗传修饰对肿瘤发生的特定贡献仍在研究中。在肝细胞癌（HCC）中，与其他肿瘤类型一样，记录了DNA甲基化改变。我们旨在鉴定HCC中的高甲基化CPG，评估其在其他肿瘤类型中的特异性，并研究其对基因表达的影响。为此，分析了来自HCC，其他肝脏疾病和27种肿瘤类型的公共甲基团以及TCGA-LIHC和GTEX的表达数据。这项研究确定了与对照肝组织相比，在HCC中高甲基化的39个CpG位点，并且位于启动子，基因体和基因间CpG岛中。值得注意的是，这些CPG在健康的肝组织和其他正常组织中主要是未甲基化的。与其他27种肿瘤的比较分析显示，常见和HCC特异性高甲基化的CPG。有趣的是，HCC甲基化基因在不同的健康组织中显示出最小的表达，在相应肿瘤中表达水平的边缘变化。这些发现证实了先前关于DNA高甲基化对癌症基因表达调节的影响有限的证据。它还突出了允许在癌变期间正常未表现的基因中选择组织特异性甲基化标记的机制的存在。总体而言，我们的研究有助于证明癌症表观遗传学的复杂性，强调需要更好地了解DNA甲基化，基因表达动力学和肿瘤发生之间的相互作用。
Abstract
DNA methylation is crucial for chromatin structure, transcription regulation and genome stability, defining cellular identity. Aberrant hypermethylation of CpG-rich regions is common in cancer, influencing gene expression. However, the specific contributions of individual epigenetic modifications to tumorigenesis remain under investigation. In hepatocellular carcinoma (HCC), DNA methylation alterations are documented as in other tumor types. We aimed to identify hypermethylated CpGs in HCC, assess their specificity across other tumor types, and investigate their impact on gene expression. To this end, public methylomes from HCC, other liver diseases, and 27 tumor types as well as expression data from TCGA-LIHC and GTEx were analyzed. This study identified 39 CpG sites that were hypermethylated in HCC compared to control liver tissue, and were located within promoter, gene bodies, and intergenic CpG islands. Notably, these CpGs were predominantly unmethylated in healthy liver tissue and other normal tissues. Comparative analysis with 27 other tumors revealed both common and HCC-specific hypermethylated CpGs. Interestingly, the HCC-hypermethylated genes showed minimal expression in the different healthy tissues, with marginal changes in the level of expression in the corresponding tumors. These findings confirm previous evidence on the limited influence of DNA hypermethylation on gene expression regulation in cancer. It also highlights the existence of mechanisms that allow the selection of tissue-specific methylation marks in normally unexpressed genes during carcinogenesis. Overall, our study contributes to demonstrate the complexity of cancer epigenetics, emphasizing the need of better understanding the interplay between DNA methylation, gene expression dynamics, and tumorigenesis.