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Consequences of VHL Loss on Global DNA Methylome

Claire M Robinson1,2, Francois Lefebvre3, Betty P Poon1,2

  • 1Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Room 1510, M5G1M1, Toronto, Ontario, Canada.

Scientific Reports
|February 22, 2018
PubMed

Insights

Loss of the VHL gene in clear-cell renal cell carcinoma (ccRCC) alters DNA methylation, impacting hypoxia-inducible factor (HIF) binding and gene expression. Hypoxia alone has minimal effects on global DNA methylation in ccRCC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Clear-cell renal cell carcinoma (ccRCC) is linked to VHL gene mutations and hypoxia, leading to HIF stabilization and oncogenesis.
  • DNA methylation alterations are observed in ccRCC, but their mechanisms and impact on gene expression remain unclear.

Purpose of the Study:

  • To investigate how VHL loss and hypoxia affect DNA methylation and HIF binding in ccRCC.
  • To identify genes whose expression correlates with DNA methylation changes in ccRCC.

Main Methods:

  • Analysis of DNA methylation status at hypoxia-responsive elements (HREs).
  • Assessment of HIF binding in relation to DNA methylation.
  • Gene expression analysis in ccRCC patient samples.
  • Comparison of DNA methylation changes induced by VHL loss versus hypoxia.

Main Results:

  • CpG methylation within HREs significantly influences HIF binding.
  • VHL loss causes substantial alterations in the ccRCC DNA methylome.
  • Hypoxia has limited impact on global DNA methylation compared to VHL loss.
  • Expression of genes like VEGF and TGF correlates with DNA methylation changes in ccRCC.

Conclusions:

  • VHL loss is a primary driver of global DNA methylation alterations in ccRCC.
  • These methylation changes contribute to ccRCC progression by affecting gene expression, including hypoxia-responsive genes.

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