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PARP1 Hinders Histone H2B Occupancy at the NFATc1 Promoter to Restrain Osteoclast Differentiation
Author(s) -
Wang Chun,
Xiao Jianqiu,
Nowak Kathrin,
Gunasekera Kapila,
Alippe Yael,
Speckman Sheree,
Yang Tong,
Kress Dustin,
AbuAmer Yousef,
Hottiger Michael O.,
Mbalaviele Gabriel
Publication year - 2020
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3927
Subject(s) - rankl , transcription factor , biology , histone , microbiology and biotechnology , activator (genetics) , histone h2b , h3k4me3 , cancer research , chemistry , receptor , biochemistry , gene expression , promoter , gene
ABSTRACT Induction of nuclear factor of activated T cell cytoplasmic 1 (NFATc1) by macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL) is essential for macrophage differentiation into osteoclasts (OCs), but the underlying mechanisms remain unclear. The ability of poly(ADP‐ribose) polymerase 1 (PARP1) to poly‐ADP‐ribosylate NFATc1 in T cells prompted us to investigate the PARP1 and NFATc1 interaction during osteoclastogenesis. However, extensive studies failed to directly link PARP1 to NFATc1. A combination of transcriptomics and proteomics studies was then used to identify PARP1 targets under these conditions. These unbiased approaches in conjunction with site‐directed mutagenesis studies revealed that PARP1 inhibited NFATc1 expression and OC formation by ADP‐ribosylating histone H2B at serine 7 and decreasing the occupancy of this histone variant at the NFATc1 promoter. The anti‐osteoclastogenic function of PARP1 was confirmed in vivo in several mouse models of PARP1 loss‐of‐function or gain‐of‐function, including a novel model in which PARP1 was conditionally ablated in myeloid cells. Thus, PARP1 ADP‐ribosylates H2B to negatively regulate NFATc1 expression and OC differentiation. © 2019 American Society for Bone and Mineral Research.