肝细胞癌中的全基因组CpG甲基化分析鉴定出与组织和肿瘤类型特异性相关的标记，与基因表达无关

Comprehensive in silico CpG methylation analysis in hepatocellular carcinoma identifies tissue- and tumor-type specific marks disconnected from gene expression

JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY

影响因子:4.3

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

DOI: 10.1007/s13105-024-01045-8

摘要

DNA甲基化对于染色质结构、转录调控和基因组稳定性至关重要，定义了细胞的身份。异常的CpG富集区域的过度甲基化在癌症中很常见，影响基因表达。然而，单个表观遗传修饰对肿瘤发生的具体贡献仍在研究中。在肝细胞癌（HCC）中，DNA甲基化的变化已被报道，与其他肿瘤类型类似。我们的目标是识别HCC中的过甲基化CpG位点，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、其他肝病以及27种肿瘤类型的公开甲基组数据，以及来自TCGA-LIHC和GTEx的表达数据。本研究鉴定出39个CpG位点，在HCC中相较于对照肝组织表现出过甲基化，这些位点位于启动子、基因体和基因间的CpG岛中。值得注意的是，这些CpGs在健康肝组织和其他正常组织中主要未甲基化。与27种其他肿瘤的比较分析显示，存在一些共同的和HCC特异的过甲基化CpG位点。有趣的是，HCC中过甲基化的基因在不同的健康组织中几乎无表达，而在相应肿瘤中的表达水平变化也很有限。这些发现证实了先前关于DNA过甲基化在癌症中对基因表达调控影响有限的证据，也突显了在癌变过程中，存在允许选择组织特异性甲基化标记的机制，尤其是在通常不表达的基因中。总体而言，我们的研究有助于展示癌症表观遗传学的复杂性，强调了深入理解DNA甲基化、基因表达动态与肿瘤发生之间相互关系的必要性。

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.