A pre-neoplastic epigenetic field defect in HCV-infected liver at transcription factor binding sites and polycomb targets.
A pre-neoplastic epigenetic field defect in HCV-infected liver at transcription factor binding sites and polycomb targets.
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DOI：
10.1038/onc.2016.340
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发表时间：
2017-04-06
期刊：
影响因子：
8
通讯作者：
Greally JM
中科院分区：
文献类型：
--
作者：
Wijetunga NA;Pascual M;Tozour J;Delahaye F;Alani M;Adeyeye M;Wolkoff AW;Verma A;Greally JM
丙型肝炎病毒（HCV）感染患者发生肝细胞癌（HCC）的易感性与病毒感染、炎症和时间有关。多灶性、遗传上不同的肿瘤的发展提示了影响整个肝脏的视野缺损。介导这种场缺陷的分子磁化率尚不清楚。长期细胞重编程的一个潜在介质是转录的遗传（表观遗传）调节，例如DNA甲基化。我们研究了HCV感染的肝脏与对照组、未感染的肝脏和HCC相比的表观遗传和转录变化，使我们能够识别肿瘤前的表观遗传和转录事件。我们发现HCV感染的肝脏具有针对肝细胞中活性的候选增强子的DNA甲基化的获得模式，其富含FOXA 1，FOXA 2和HNF 4A转录因子的结合位点。这些增强子可以被细分为那些与肝癌相关的基因或与干细胞发育相关的基因的近端增强子，后者的区别在于增加的CG二核苷酸密度和多梳介导的抑制，表现为额外获得组蛋白H3赖氨酸27三甲基化（H3K27me3）。对我们样本的转录研究表明，增强子处DNA甲基化的增加与局部基因表达的降低有关，结果在癌症基因组图谱的独立样本中得到验证。在HepG2细胞中使用EZH2抑制剂GSK343的H3K27me3的药理学消耗抑制了细胞生长，并且还揭示了局部获得性DNA甲基化不依赖于polycomb介导的抑制的存在。这些结果支持HCV感染影响转录因子与基因组中同源位点结合的模型，随后局部获得DNA甲基化，并在CG密集顺式调控序列的子集上增加polycomb的抑制性影响。这些表观遗传事件发生在肿瘤转化之前，导致HCV感染肝脏中可能是可逆的表观遗传场缺陷。
The predisposition of patients with Hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) involves components of viral infection, inflammation and time. The development of multifocal, genetically distinct tumours is suggestive of a field defect affecting the entire liver. The molecular susceptibility mediating such a field defect is not understood. One potential mediator of long-term cellular reprogramming is heritable (epigenetic) regulation of transcription, exemplified by DNA methylation. We studied epigenetic and transcriptional changes in HCV-infected livers in comparison with control, uninfected livers and HCC, allowing us to identify pre-neoplastic epigenetic and transcriptional events. We find the HCV-infected liver to have a pattern of acquisition of DNA methylation targeted to candidate enhancers active in liver cells, enriched for the binding sites of the FOXA1, FOXA2 and HNF4A transcription factors. These enhancers can be subdivided into those proximal to genes implicated in liver cancer or to genes involved in stem cell development, the latter distinguished by increased CG dinucleotide density and polycomb-mediated repression, manifested by the additional acquisition of histone H3 lysine 27 trimethylation (H3K27me3). Transcriptional studies on our samples showed that the increased DNA methylation at enhancers was associated with decreased local gene expression, results validated in independent samples from The Cancer Genome Atlas. Pharmacological depletion of H3K27me3 using the EZH2 inhibitor GSK343 in HepG2 cells suppressed cell growth and also revealed that local acquired DNA methylation was not dependent upon the presence of polycomb-mediated repression. The results support a model of HCV infection influencing the binding of transcription factors to cognate sites in the genome, with consequent local acquisition of DNA methylation, and the added repressive influence of polycomb at a subset of CG-dense cis-regulatory sequences. These epigenetic events occur before neoplastic transformation, resulting in what may be a pharmacologically reversible epigenetic field defect in HCV-infected liver.