Repression of Runx2 function by TGF-beta through recruitment of class II histone deacetylases by Smad3.
Transforming growth factor-beta (TGF-beta) inhibits osteoblast differentiation through inhibition of the function of Runx2 (Cbfa1) by Smad3. The mechanism through which TGF-beta/Smad3 inhibits Runx2 function has not been characterized. We show that TGF-beta induces histone deacetylation, primarily of histone H4, at the osteocalcin promoter, which is repressed by TGF-beta, and that histone deacetylation is required for repression of Runx2 by TGF-beta. This repression occurs through the action of the class IIa histone deacetylases (HDAC)4 and 5, which are recruited through interaction with Smad3 to the Smad3/Runx2 complex at the Runx2-binding DNA sequence. Accordingly, HDAC4 or 5 is required for efficient TGF-beta-mediated inhibition of Runx2 function and is involved in osteoblast differentiation. Our results indicate that class IIa HDACs act as corepressors for TGF-beta/Smad3-mediated transcriptional repression of Runx2 function in differentiating osteoblasts and are cell-intrinsic regulators of osteoblast differentiation.
Department of Cell and Tissue Biology, Department of Anatomy, Programs in Cell Biology and Developmental Biology, University of California, San Francisco, CA 94143-0512, USA.
Jong Seok
JS
Kang
Tamara
T
Alliston
Rachel
R
Delston
Rik
R
Derynck
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins / Q000502:physiology*; D006655:Histone Deacetylases / Q000145:classification* / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000235:genetics; D011401:Promoter Regions, Genetic; D051900:Smad3 Protein; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D015675:Osteocalcin; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases