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Runx2 (Cbfa1, AML-3) interacts with histone deacetylase 6 and represses the p21(CIP1/WAF1) promoter

Jennifer J Westendorf1, S Kaleem Zaidi, Jonathan E Cascino

  • 1Department of Orthopaedic Surgery. University of Minnesota Cancer Center. College of Biological Sciences. Graduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, Minnesota 55455, USA. weste047@umn.edu

Molecular and Cellular Biology
|October 23, 2002
PubMed

Insights

Runx2 transcription factor represses p21 expression via its carboxy-terminus. This interaction recruits HDAC6, a histone deacetylase, to chromatin, regulating osteoblast gene expression.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Runx2 is a crucial transcription factor for osteoblast development.
  • Runx2 regulates tissue-specific gene expression through interactions with coactivators and corepressors.

Purpose of the Study:

  • To identify repressible gene targets of Runx2.
  • To elucidate the mechanism of Runx2-mediated repression, focusing on the role of its carboxy-terminal domain and interactions with histone deacetylases.

Main Methods:

  • Promoter analysis to identify Runx2-repressible targets.
  • Reporter gene assays to assess the function of the Runx2 carboxy-terminal repression domain.
  • Co-immunoprecipitation and colocalization studies to investigate protein interactions.
  • Treatment with histone deacetylase inhibitors (trichostatin A and trapoxin B).

Main Results:

  • The p21(CIP/WAF1) promoter was identified as a direct Runx2 target for repression.
  • A novel carboxy-terminal repression domain of Runx2, distinct from known domains, mediates p21 repression.
  • This domain's repressive activity is sensitive to trichostatin A but not trapoxin B.
  • Histone deacetylase 6 (HDAC6) specifically interacts with the Runx2 carboxy terminus and is recruited to chromatin.
  • HDAC6 colocalizes and coimmunoprecipitates with Runx2 in osteoblasts.
  • Runx2 carboxy terminus is essential for maximal p21 promoter repression in preosteoblasts.

Conclusions:

  • Runx2 directly represses the p21 promoter through its carboxy-terminal domain.
  • HDAC6 is identified as the first transcription factor to interact with Runx2.
  • HDAC6 binding to Runx2 in differentiating osteoblasts is critical for regulating tissue-specific gene expression, specifically p21 repression.

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