RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1β- and RNA-dependent co-activator of osteoclast gene expression

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 receptor activator of nuclear factor kappa-Β (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NFkB 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 PGC1b with the NCoR/HDAC3 complex, resulting in activation of PGC1b and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12 that 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.