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Cited by 102Epigenetics and DNA MethylationGenomics and Chromatin DynamicsCancer-related molecular mechanisms research

Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma

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Hlady, Ryan A., Sathyanarayan, Aishwarya, Thompson, Joyce J., Zhou, Dan, Wu, Qunfeng, Pham, Kien, Lee, Jeong‐Heon, Liu, Chen +1 more·2019·Hepatology
DOI 10.1002/hep.30211PMC PMC6351162
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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.

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Crossref · 10.1002/hep.30211

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  • The role of epigenetic dysregulation in driving the aberrant activity of CREs and retrotransposons in HCC remains incompletely understood.

    “the role of epigenetic dysregulation in driving the aberrant activity of CREs and retrotransposons in HCC remains incompletely understood50–52,93.”

    From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [93]

    The Abstract says the HCC epigenome remains understudied and reports epigenetic remodeling of enhancers, supporting the claim about incomplete understanding of regulatory-element activity. The passages do not address retrotransposon activity, so that part of the claim is not supported by this source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Reference and alternative CGI promoters have divergent H3K4me3 and H3K27ac marks around the NDR at TSSs in HCC patients and HepG2 cells.

    “Reference and alternative CGI promoters have divergent H3K4me3 and H3K27ac marks around the nucleosome-depleted region (NDR) at TSSs both in HCC patients6 (Fig. 4a) and HepG2 cells”

    From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [6]

    The Results section on histone modifications (page unavailable) reports H3K4me3 and H3K27ac together at promoter regions in liver disease, including HCC. It does not compare reference with alternative CGI promoters or describe divergent marks around a nucleosome-depleted region at transcription start sites. The citation is attached to the HCC-patient portion of the sentence, not the subsequent HepG2-cell portion. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Intragenic CGIs have low levels of DNA demethylase (5hmC) activity, consistent with low levels of TET1 binding.

    “Intragenic CGIs have low levels of DNA demethylase (5hmC levels) activity (Fig. 5e) measured by TET-assisted reduced RRBS (TAB-RRBS)6, which is consistent with low levels of TET1 binding”

    From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [6]

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Cites

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Cited by

Sorted by citations

Authors
Hlady, R. A., Sathyanarayan, A., Thompson, J. J., Zhou, D., Wu, Q., Pham, K., Lee, J., Liu, C., & Robertson, K. D.
Affiliations
  • Mayo Clinic (US)
  • Rutgers, The State University of New Jersey (US)
Corresponding author
Robertson, Keith D.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-01-05
Volume
69
Issue
2
Pages
639-652
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.30211
PMC
PMC6351162
OpenAlex
W2888499439
Cited by
102
References
3
Citations by year
2026: 7 · 2025: 9 · 2024: 11 · 2023: 18 · 2022: 17 · 2021: 12 · 2020: 16 · 2019: 11 · 2018: 1
FWCI
3.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Association for the Study of Liver Diseases
  • National Institute on Alcohol Abuse and Alcoholism (R01AA027179)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK110024, P30DK084567)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
Keywords
hepatocellular carcinoma, epigenome, DNA methylation, 5-hydroxymethylcytosine, histone modifications, enhancer remodeling, liver cirrhosis, catechol-O-methyltransferase, FMO3, apoptosis, H3K4me1, H3K27ac, H3K4me3, H3K27me3
MeSH terms
Epigenome, Carcinoma, Hepatocellular, Humans, Liver, Liver Cirrhosis, Liver Neoplasms, Case-Control Studies, DNA Methylation, Histone Code

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