학술논문
RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1β- and RNA-dependent co-activator of osteoclast gene expression
Document Type
article
Author
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
Source
Molecular Cell. 83(19)
Subject
Language
Abstract
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.