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

Yohei Abe; Eric R Kofman; Maria Almeida; Zhengyu Ouyang; Filipa Ponte; Jasmine R Mueller; Grisel Cruz-Becerra; Mashito Sakai; Thomas A Prohaska; Nathanael J Spann; Ana Resende-Coelho; Jason S Seidman; Joshua D Stender; Havilah Taylor; Weiwei Fan; Verena M Link; Isidoro Cobo; Johannes C M Schlachetzki; Takao Hamakubo; Kristen Jepsen; Juro Sakai; Michael Downes; Ronald M Evans; Gene W Yeo; James T Kadonaga; Stavros C Manolagas; Michael G Rosenfeld; Christopher K Glass

doi:10.1016/j.molcel.2023.08.029

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

Mol Cell. 2023 Oct 5;83(19):3421-3437.e11. doi: 10.1016/j.molcel.2023.08.029. Epub 2023 Sep 25.

Authors

Yohei Abe¹, Eric R Kofman², Maria Almeida³, Zhengyu Ouyang¹, Filipa Ponte⁴, Jasmine R Mueller², Grisel Cruz-Becerra⁵, Mashito Sakai⁶, Thomas A Prohaska⁷, Nathanael J Spann¹, Ana Resende-Coelho⁴, Jason S Seidman¹, Joshua D Stender¹, Havilah Taylor⁷, Weiwei Fan⁸, Verena M Link⁹, Isidoro Cobo¹, Johannes C M Schlachetzki¹, Takao Hamakubo¹⁰, Kristen Jepsen¹¹, Juro Sakai¹², Michael Downes⁸, Ronald M Evans⁸, Gene W Yeo², James T Kadonaga⁵, Stavros C Manolagas³, Michael G Rosenfeld⁷, Christopher K Glass¹³

Affiliations

¹ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
² Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Stem Cell Program, University of California San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA.
³ Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Department of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
⁴ Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
⁵ Department of Molecular Biology, University of California San Diego, La Jolla, CA 92093, USA.
⁶ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Biochemistry and Molecular Biology, Nippon Medical School Hospital, Tokyo 113-8602, Japan.
⁷ Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
⁸ Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁹ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Faculty of Biology, Department II, Ludwig-Maximilians Universität München, Planegg-Martinsried 82152, Germany.
¹⁰ Department of Protein-Protein Interaction Research, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo 113-8602, Japan.
¹¹ Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA.
¹² Division of Metabolic Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan; Division of Molecular Physiology and Metabolism, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
¹³ Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].

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.

Keywords: AP-1; H3K27ac; HDAC3; NCoR; NF-κB; PGC1β; RANK; co-activator; deacetylation; gene expression; non-coding RNA; osteoclast.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Co-Repressor Proteins / genetics
Gene Expression
Humans
Mice
Nuclear Receptor Co-Repressor 1 / genetics
Nuclear Receptor Co-Repressor 1 / metabolism
Osteoclasts* / metabolism
RANK Ligand / genetics
RNA*

Substances

Co-Repressor Proteins
histone deacetylase 3
RNA
RANK Ligand
Nuclear Receptor Co-Repressor 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding