Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma

Ryan A. Hlady, Aishwarya Sathyanarayan, Joyce J. Thompson, Dan Zhou, Qunfeng Wu, Kien Pham, Jeong Heon Lee, Chen Liu, Keith D Robertson

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalHepatology
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Epigenomics
Hepatocellular Carcinoma
Histone Code
dimethylaniline monooxygenase (N-oxide forming)
Liver
DNA Methylation
Post Translational Protein Processing
Liver Neoplasms
Computational Biology
Histones
Liver Diseases
Neoplasms
Cell Survival
Genome
Apoptosis
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Hepatology

Cite this

Hlady, R. A., Sathyanarayan, A., Thompson, J. J., Zhou, D., Wu, Q., Pham, K., ... Robertson, K. D. (Accepted/In press). Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma. Hepatology. https://doi.org/10.1002/hep.30211

Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma. / Hlady, Ryan A.; Sathyanarayan, Aishwarya; Thompson, Joyce J.; Zhou, Dan; Wu, Qunfeng; Pham, Kien; Lee, Jeong Heon; Liu, Chen; Robertson, Keith D.

In: Hepatology, 01.01.2019.

Research output: Contribution to journalArticle

Hlady RA, Sathyanarayan A, Thompson JJ, Zhou D, Wu Q, Pham K et al. Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma. Hepatology. 2019 Jan 1. https://doi.org/10.1002/hep.30211
Hlady, Ryan A. ; Sathyanarayan, Aishwarya ; Thompson, Joyce J. ; Zhou, Dan ; Wu, Qunfeng ; Pham, Kien ; Lee, Jeong Heon ; Liu, Chen ; Robertson, Keith D. / Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma. In: Hepatology. 2019.
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