- Abe, Yohei;
- Kofman, Eric R;
- Almeida, Maria;
- Ouyang, Zhengyu;
- Ponte, Filipa;
- Mueller, Jasmine R;
- Cruz-Becerra, Grisel;
- Sakai, Mashito;
- Prohaska, Thomas A;
- Spann, Nathanael J;
- Resende-Coelho, Ana;
- Seidman, Jason S;
- Stender, Joshua D;
- Taylor, Havilah;
- Fan, Weiwei;
- Link, Verena M;
- Cobo, Isidoro;
- Schlachetzki, Johannes CM;
- Hamakubo, Takao;
- Jepsen, Kristen;
- Sakai, Juro;
- Downes, Michael;
- Evans, Ronald M;
- Yeo, Gene W;
- Kadonaga, James T;
- Manolagas, Stavros C;
- Rosenfeld, Michael G;
- Glass, Christopher K
The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.