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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >DNA Methylation Signatures Reveal the Diversity of Processes Remodeling Hepatocellular Carcinoma Methylomes
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DNA Methylation Signatures Reveal the Diversity of Processes Remodeling Hepatocellular Carcinoma Methylomes

机译：DNA 甲基化特征揭示了重塑肝细胞癌甲基化组的过程的多样性

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BACKGROUND AND AIMS: DNA methylation patterns are highly rearranged in HCCs. However, diverse sources of variation are intermingled in cancer methylomes, precluding the precise characterization of underlying molecular mechanisms. We developed a computational framework (methylation signature analysis with independent component analysis MethICA) leveraging independent component analysis to disentangle the diverse processes contributing to DNA methylation changes in tumors. APPROACH AND RESULTS: Applied to a collection of 738 HCCs, MethICA unraveled 13 stable methylation components preferentially active in specific chromatin states, sequence contexts, and replication timings. These included signatures of general processes associated with sex and age but also signatures related to specific driver events and molecular subgroups. Catenin beta 1 mutations were major modulators of methylation patterns in HCC, characterized by a targeted hypomethylation of transcription factor 7-bound enhancers in the vicinity of Wnt target genes as well as a widespread hypomethylation of late-replicated partially methylated domains. By contrast, demethylation of early replicated highly methylated domains was a signature of replication stress, leading to an extensive hypomethylator phenotype in cyclin-activated HCC. Inactivating mutations of the chromatin remodeler AT-rich interactive domain-containing protein 1A were associated with epigenetic silencing of differentiation-promoting transcriptional networks, also detectable in cirrhotic liver. Finally, a hypermethylation signature targeting polycomb-repressed chromatin domains was identified in the G1 molecular subgroup with progenitor features. CONCLUSIONS: This study elucidates the diversity of processes remodeling HCC methylomes and reveals the epigenetic and transcriptional impact of driver alterations.
机译：背景和目的：DNA甲基化模式在HCC中高度重排。然而，癌症甲基化组中混合了多种变异来源，从而排除了对潜在分子机制的精确表征。我们开发了一个计算框架（具有独立成分分析的甲基化特征分析 [MethICA]），利用独立成分分析来解开导致肿瘤中 DNA 甲基化变化的不同过程。方法和结果：应用于 738 个 HCC 的集合，MethICA 揭示了 13 种稳定的甲基化成分，这些成分在特定的染色质状态、序列环境和复制时间中具有优先活性。这些包括与性别和年龄相关的一般过程的特征，以及与特定驱动事件和分子亚组相关的特征。连环蛋白 β1 突变是 HCC 甲基化模式的主要调节剂，其特征是 Wnt 靶基因附近的转录因子 7 结合增强子的靶向低甲基化以及晚期复制的部分甲基化结构域的广泛低甲基化。相比之下，早期复制的高度甲基化结构域的去甲基化是复制应激的特征，导致细胞周期蛋白激活的 HCC 中广泛的低甲基化表型。染色质重塑剂富含 AT 的相互作用结构域蛋白 1A 的失活突变与促进分化的转录网络的表观遗传沉默有关，在肝硬化肝中也可检测到。最后，在具有祖细胞特征的G1分子亚群中鉴定出靶向多梳抑制染色质结构域的高甲基化特征。结论：本研究阐明了重塑HCC甲基化组的过程的多样性，并揭示了驱动改变的表观遗传和转录影响。

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