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SRC proximal and core promoter elements dictate TAF1 dependence and transcriptional repression by histone deacetylase

Scott M Dehm1, Traci L Hilton, Edith H Wang

  • 1Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada.

Molecular and Cellular Biology
|March 3, 2004
PubMed

Insights

Histone deacetylase inhibitors (HDIs) repress gene transcription in cancer cells. This study reveals that promoter architecture, particularly core promoter elements, mediates this repression, implicating TAF1 dependence.

Area of Science:

  • Epigenetics
  • Cancer Biology
  • Molecular Biology

Background:

  • Histone deacetylase inhibitors (HDIs) are known to induce significant cellular responses in cancer, including cell cycle arrest, differentiation, and apoptosis.
  • These effects are driven by profound alterations in gene expression patterns, but the precise mechanisms of transcriptional activation and repression by HDIs remain unclear.
  • The human SRC gene promoter has been utilized as a model system to investigate HDI-mediated transcriptional repression.

Purpose of the Study:

  • To elucidate the mechanism underlying Histone deacetylase inhibitor (HDI)-mediated transcriptional repression of the human SRC gene.
  • To identify the specific promoter elements responsible for HDI-induced gene silencing.
  • To investigate the role of TAF1 in HDI-mediated transcriptional regulation.

Main Methods:

  • Comparative analysis of tissue-specific and housekeeping SRC promoters.
  • Promoter-swapping experiments using the HDI-inducible p21(WAF1) promoter.
  • Assessment of TAF1 dependence in SRC and chimeric promoter constructs.

Main Results:

  • Both SRC promoters, despite differences, share core promoter elements and exhibit TAF1-dependent transcription.
  • Core and proximal promoter elements of the SRC gene are implicated in HDI-mediated repression.
  • Chimeric SRC-p21(WAF1) promoter constructs showed both HDI-mediated repression and TAF1 dependence.

Conclusions:

  • The overall promoter architecture, not just discrete elements, dictates HDI-mediated transcriptional repression.
  • Core promoter elements play a crucial role in mediating the repressive effects of HDIs.
  • TAF1 is implicated as a key mediator in the pathway of HDI-induced gene repression.

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