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c-Myc regulates the coordinated transcription of brain disease-related PDCD10-SERPINI1 bidirectional gene pair

Ping-Yen Chen1, Wun-Shaing W Chang, Yiu-Kay Lai

  • 1National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan, ROC.

Molecular and Cellular Neurosciences
|May 16, 2009
PubMed

Insights

The oncogenic c-Myc transcription factor regulates two brain disease genes, SERPINI1 and PDCD10. Its binding to a bidirectional promoter is affected by DNA methylation, impacting gene expression in central nervous system diseases.

Area of Science:

  • Genetics
  • Molecular Biology
  • Neuroscience

Background:

  • The SERPINI1 gene (protease inhibitor) is downregulated in brain tumors.
  • The PDCD10 gene (programmed cell death) is mutated in cerebral cavernous malformation.
  • These two genes are located adjacently on human chromosome 3q26.

Purpose of the Study:

  • To investigate the regulatory mechanism of the bidirectional promoter between SERPINI1 and PDCD10.
  • To identify transcription factors involved in the coordinated expression of these two genes.
  • To explore the role of c-Myc and DNA methylation in regulating SERPINI1 and PDCD10 expression.

Main Methods:

  • Analysis of the intergenic region between SERPINI1 and PDCD10.
  • Identification of a minimal bidirectional promoter.
  • Electrophoretic mobility shift assays (EMSA) to study transcription factor binding.
  • Investigation of DNA methylation effects on transcription factor binding.

Main Results:

  • A 175-bp GC-rich bidirectional promoter was identified in the intergenic region.
  • The oncogenic c-Myc transcription factor binds to a non-canonical E-box (5'-CATGCG-3') within the promoter.
  • Methylation at a specific cytosine within the E-box significantly inhibits c-Myc binding.
  • c-Myc binding drives the expression of both SERPINI1 and PDCD10.

Conclusions:

  • c-Myc plays a crucial role in the coordinated transcription of the PDCD10-SERPINI1 gene pair.
  • DNA methylation of the E-box can modulate c-Myc binding and gene expression.
  • These findings suggest c-Myc's involvement in the differential expression of these genes in central nervous system diseases like brain cancer.

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