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Induction and Testing of Hypoxia in Cell Culture
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VHL inactivation without hypoxia is sufficient to achieve genome hypermethylation

Artem V Artemov1, Nadezhda Zhigalova2, Svetlana Zhenilo2

  • 1Institute of Bioengineering, Research Center of Biotechnology RAS, Moscow, Russia. artem.v.artemov@gmail.com.

Scientific Reports
|July 15, 2018
PubMed

Insights

VHL inactivation causes genome-wide DNA hypermethylation, even without hypoxia. This epigenetic change affects gene expression, particularly at transcription factor binding sites, impacting renal carcinoma development.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Von Hippel-Lindau (VHL) gene inactivation is crucial in renal cell carcinoma (RCC) development.
  • VHL normally suppresses hypoxia-inducible factor 1-alpha (HIF1a) in normoxia.
  • Hypoxia and VHL inactivation are linked to DNA hypermethylation and altered gene expression.

Purpose of the Study:

  • To investigate the effects of VHL inactivation on gene expression and DNA methylation.
  • To determine if VHL inactivation causes DNA hypermethylation independently of hypoxia.

Main Methods:

  • VHL gene inactivation using CRISPR/Cas9 gene editing.
  • Analysis of genome-wide gene expression and DNA methylation patterns.
  • Identification of enriched DNA methylation sites and associated transcription factor binding sites.

Main Results:

  • VHL inactivation induced significant genome-wide DNA hypermethylation, irrespective of oxygen levels.
  • Hypermethylated cytosines were distributed broadly, with enrichment at AP-1 binding sites.
  • Increased gene expression correlated with hypermethylated cytosine enrichment at specific transcription factor binding sites.
  • Promoter hypermethylation was observed for key regulators of transcription and DNA methylation, such as SALL3, leading to decreased gene expression.

Conclusions:

  • VHL inactivation is sufficient to cause widespread DNA hypermethylation and alter gene expression patterns in renal cells.
  • These epigenetic modifications, driven by VHL loss, likely contribute to oncogenesis in renal carcinomas.
  • The findings highlight a direct link between VHL status, DNA methylation, and transcriptional dysregulation in cancer.

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