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 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. [Display omitted] •NCoR is required for osteoclast differentiation and normal bone density•RANK signaling converts NCoR/HDAC3 co-repressor complexes to co-activator complexes•RANK signaling induces RNA-dependent interaction of NCoR/HDAC3 with PGC1β•The major function of NCoR in osteoclasts is RANKL-dependent gene activation Nuclear receptor co-repressor (NCoR) is found to maintain normal bone density by co-activating RANKL-dependent gene transcription in osteoclasts. Abe et al. resolve this paradox by demonstrating that RANKL induces RNA-dependent assembly of an NCoR/HDAC3/PGC1β complex that co-activates NF-κB and AP-1 target genes required for osteoclast differentiation.