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This study identifies a new SETD3 signaling pathway regulating VEGF expression. SETD3 methylates FoxM1, impacting its role in gene expression under varying oxygen levels.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Epigenetics

Background:

  • Protein lysine methyltransferases (PKMTs) regulate biological processes.
  • SETD3 is a PKMT involved in gene regulation.
  • VEGF expression is critical in various physiological and pathological conditions.

Purpose of the Study:

  • To identify novel SETD3 interacting proteins.
  • To elucidate the role of SETD3 in regulating VEGF expression.
  • To investigate the mechanism of SETD3-mediated gene regulation under hypoxia.

Main Methods:

  • Proteomic analysis to identify SETD3 interacting proteins.
  • Chromatin immunoprecipitation (ChIP) assays to assess protein enrichment on the VEGF promoter.
  • Western blotting to evaluate protein levels under different conditions.

Main Results:

  • 172 novel SETD3 interacting proteins were identified.
  • SETD3 directly binds and methylates the transcription factor FoxM1.
  • SETD3 and FoxM1 are recruited to the VEGF promoter under normoxia and dissociate under hypoxia, correlating with VEGF expression changes.
  • SETD3 expression is downregulated under hypoxic conditions.

Conclusions:

  • SETD3 functions as a methylation-based regulator of VEGF expression.
  • A novel SETD3-FoxM1-VEGF signaling axis at the chromatin level is revealed.
  • This pathway plays a crucial role in adapting VEGF expression to oxygen availability.