表观基因组
表观遗传学
生物
DNA甲基化
H3K4me3
组蛋白
增强子
表观遗传学
癌症研究
神经发生的表观遗传调控
遗传学
转录因子
发起人
基因表达
基因
染色质重塑
作者
Ryan A. Hlady,Aishwarya Sathyanarayan,Joyce J. Thompson,Dan Zhou,Qiang-Sheng Wu,Kien Pham,Jeong Heon Lee,Chen Liu,Keith D. Robertson
出处
期刊:Hepatology
[Wiley]
日期:2019-01-05
卷期号:69 (2): 639-652
被引量:61
摘要
Disruption of epigenetic mechanisms has been intimately linked to the etiology of human cancer. Understanding how these epigenetic mechanisms (including DNA methylation [5mC], hydroxymethylation [5hmC], and histone post‐translational modifications) work in concert to drive cancer initiation and progression remains unknown. Hepatocellular carcinoma (HCC) is increasing in frequency in Western countries but lacks efficacious treatments. The epigenome of HCC remains understudied. To better understand the epigenetic underpinnings of HCC, we performed a genome‐wide assessment of 5mC, 5hmC, four histone modifications linked to promoter/enhancer function (H3K4me1, H3K27ac, H3K4me3, and H3K27me3), and transcription across normal, cirrhotic, and HCC liver tissue. Implementation of bioinformatic strategies integrated these epigenetic marks with each other and with transcription to provide a comprehensive epigenetic profile of how and when the liver epigenome is perturbed during progression to HCC. Our data demonstrate significant deregulation of epigenetic regulators combined with disruptions in the epigenome hallmarked by profound loss of 5hmC, locus‐specific gains in 5mC and 5hmC, and markedly altered histone modification profiles, particularly remodeling of enhancers. Data integration demonstrates that these marks collaborate to influence transcription (e.g., hyper‐5hmC in HCC‐gained active enhancers is linked to elevated expression) of genes regulating HCC proliferation. Two such putative epigenetic driver loci identified through our integrative approach, COMT and FMO3 , increase apoptosis and decrease cell viability in liver‐derived cancer cell lines when ectopically re‐expressed. Conclusion : Altogether, integration of multiple epigenetic parameters is a powerful tool for identifying epigenetically regulated drivers of HCC and elucidating how epigenome deregulation contributes to liver disease and HCC.
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