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A role for cofactor-cofactor and cofactor-histone interactions in targeting p300, SWI/SNF and Mediator for

Zhi-Qing Huang1, Jiwen Li, Laurent M Sachs

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

The EMBO Journal
|May 3, 2003
PubMed

Insights

Nuclear receptors (NRs) recruit cofactors like CBP/p300 and SWI/SNF for gene activation. This study reveals that p300 targets SWI/SNF and Mediator complexes, coordinating cofactor recruitment through histone acetylation and cofactor interactions.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Gene Regulation

Background:

  • Nuclear receptors (NRs) are crucial transcription factors that regulate gene expression.
  • NR-mediated transcription requires a complex interplay of cofactors, including histone acetyltransferases (e.g., CBP/p300), chromatin remodelers (e.g., SWI/SNF), and the Mediator complex.
  • The precise mechanisms by which NRs recruit these multiple cofactors to target gene promoters remain incompletely understood.

Purpose of the Study:

  • To elucidate the recruitment mechanism of multiple cofactors by nuclear receptors during transcriptional activation.
  • To investigate the role of p300 and SWI/SNF in hormone-dependent gene activation.
  • To determine the interplay between cofactors and histone modifications in the recruitment process.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) assays to assess the promoter targeting of NRs and cofactors.
  • Biochemical assays to study protein-protein interactions between cofactors.
  • Analysis of DNA topology changes associated with SWI/SNF recruitment.
  • Assessment of histone acetyltransferase activity of p300 and its role in cofactor recruitment.

Main Results:

  • Hormone-dependent activation by androgen receptor (AR) and thyroid hormone receptor (TR) involves the recruitment of SRC family members, p300, SWI/SNF, and Mediator to target promoters.
  • SWI/SNF recruitment leads to chromatin remodeling, evidenced by altered DNA topology.
  • Both SWI/SNF and p300 histone acetylase activity are essential for hormone-dependent transcriptional activation.
  • p300 acts as a scaffold, targeting SWI/SNF and Mediator to chromatin, with p300 itself being recruited via SRC coactivators.
  • Histone acetylation by CBP/p300 facilitates the subsequent recruitment of SWI/SNF and Mediator complexes.

Conclusions:

  • Cofactor recruitment to NRs is not solely mediated by direct interactions with the receptors.
  • p300 plays a central role in coordinating the recruitment of SWI/SNF and Mediator complexes.
  • Cofactor-cofactor interactions and histone modifications are critical for orchestrating the assembly of the transcriptional machinery.
  • This study provides a model for how multiple essential cofactors are brought together at target gene promoters for NR-mediated transcription.

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