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Repression of Runx2 function by TGF‐β through recruitment of class II histone deacetylases by Smad3
Author(s) -
Kang Jong Seok,
Alliston Tamara,
Delston Rachel,
Derynck Rik
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600729
Subject(s) - runx2 , psychological repression , hdac4 , histone , transforming growth factor beta , chemistry , microbiology and biotechnology , histone h4 , biology , transforming growth factor , osteoblast , histone deacetylase , biochemistry , dna , gene expression , gene , in vitro
Transforming growth factor‐β (TGF‐β) inhibits osteoblast differentiation through inhibition of the function of Runx2 (Cbfa1) by Smad3. The mechanism through which TGF‐β/Smad3 inhibits Runx2 function has not been characterized. We show that TGF‐β induces histone deacetylation, primarily of histone H4, at the osteocalcin promoter, which is repressed by TGF‐β, and that histone deacetylation is required for repression of Runx2 by TGF‐β. 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‐β‐mediated inhibition of Runx2 function and is involved in osteoblast differentiation. Our results indicate that class IIa HDACs act as corepressors for TGF‐β/Smad3‐mediated transcriptional repression of Runx2 function in differentiating osteoblasts and are cell‐intrinsic regulators of osteoblast differentiation.