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Loss of Tet1-Associated 5-Hydroxymethylcytosine Is Concomitant with Aberrant Promoter Hypermethylation in Liver

John P Thomson1, Raffaele Ottaviano1, Elif B Unterberger2

  • 1MRC Human Genetics Unit at the Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, United Kingdom.

Cancer Research
|May 20, 2016
PubMed

Insights

Aberrant DNA hypermethylation in liver cancer is preceded by changes in 5-hydroxymethylcytosine (5hmC) and H3K27me3. Reduced Tet1 activity may drive these epigenetic shifts, impacting gene transcription during tumor progression.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Genomics

Background:

  • Aberrant DNA hypermethylation of CpG islands (CGI) is common in human tumors, primarily affecting repressed genes.
  • The precise events initiating CGI hypermethylation in cancer remain unclear.
  • Understanding these early epigenetic changes is crucial for deciphering cancer development.

Purpose of the Study:

  • To investigate the temporal sequence of epigenetic and transcriptomic alterations during liver carcinogenesis in a mouse model.
  • To identify predictive markers for CGI hypermethylation events.
  • To explore the role of Tet1 in epigenetic dysregulation during hepatocarcinogenesis.

Main Methods:

  • Temporal tracking of epigenetic modifications (5-hydroxymethylcytosine, H3K27me3) and gene expression in a mouse model of liver cancer.
  • Analysis of livers from Tet1-deficient mice.
  • Correlation analysis between DNA methylation changes, histone modifications, and transcriptional activity in tumors.

Main Results:

  • Hypermethylation of CGIs was preceded by enrichment of 5-hydroxymethylcytosine (5hmC) and H3K27me3 at silenced promoters.
  • During cancer progression, CGIs showed a loss of 5hmC before hypermethylation, while retaining H3K27me3.
  • Tet1 deficiency led to reduced promoter core 5hmC, mirroring observations in liver tumors with decreased Tet1 protein levels.
  • Dynamic H3K27me3 changes strongly correlated with tumor-specific gene expression changes, not DNA methylation alterations.

Conclusions:

  • Loss of promoter-associated 5hmC in liver tumors may permit DNA methylation reprogramming at silent CGIs.
  • Reduced Tet1 activity is implicated in the epigenetic dysregulation observed during hepatocarcinogenesis.
  • Epigenetic reprogramming, particularly H3K27me3 dynamics, plays a significant role in regulating gene transcription during liver cancer progression.

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