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Silencing of bidirectional promoters by DNA methylation in tumorigenesis

Jingmin Shu1, Jaroslav Jelinek, Hao Chang

  • 1Department of Leukemia, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

Cancer Research
|May 19, 2006
PubMed

Insights

CpG island hypermethylation can silence two genes at once when they share a bidirectional promoter. This finding is crucial for understanding gene silencing in various cancers.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Genetics

Background:

  • CpG island methylation silences individual genes in cancer.
  • The role of this epigenetic mechanism in silencing gene pairs regulated by bidirectional promoters remains largely unknown.

Purpose of the Study:

  • To investigate the impact of CpG island methylation on gene pairs controlled by bidirectional promoters in cancer.
  • To determine if hypermethylation of bidirectional promoters leads to simultaneous silencing of associated genes.

Main Methods:

  • Screening for hypermethylated CpG islands in cancer.
  • Analyzing bidirectional gene pairs (WNT9A/CD558500, CTDSPL/BC040563, KCNK15/BF195580) using mRNA expression and methylation levels.
  • Utilizing 5-aza-2'-deoxycytidine treatment to assess hypomethylation effects.
  • Performing luciferase assays to confirm promoter bidirectionality.

Main Results:

  • Bidirectional promoters constituted 25.2% of identified hypermethylated promoters in cancer.
  • mRNA levels of analyzed gene pairs were inversely correlated with promoter methylation.
  • Hypomethylation reactivated gene expression bidirectionally.
  • Hypermethylation of WNT9A/CD558500 and CTDSPL/BC040563 promoters occurred frequently in colon cancers and acute lymphoid leukemias (ALL), respectively.
  • Methylation correlated with decreased gene expression in ALL patient samples.

Conclusions:

  • Hypermethylation of bidirectional promoter-associated CpG islands silences two genes simultaneously.
  • This simultaneous gene silencing mechanism is a significant factor in cancer epigenetics.
  • Future studies on cancer hypermethylation should consider the impact on bidirectional promoters.

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