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Nature Cell Biology 9, 1273–1285 (1 November 2007) | doi:10.1038/ncb1647

A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-|[gamma]| transactivation

Ichiro Takada , Masatomo Mihara , Miyuki Suzawa , Fumiaki Ohtake , Shinji Kobayashi , Mamoru Igarashi , Min-Young Youn , Ken-ichi Takeyama , Takashi Nakamura , Yoshihiro Mezaki , Shinichiro Takezawa , Yoshiko Yogiashi , Hirochika Kitagawa , Gen Yamada , Shinji Takada , Yasuhiro Minami , Hiroshi Shibuya , Kunihiro Matsumoto & Shigeaki Kato

Histone modifications induced by activated signalling cascades are crucial to cell-lineage decisions. Osteoblast and adipocyte differentiation from common mesenchymal stem cells is under transcriptional control by numerous factors. Although PPAR-γ (peroxisome proliferator activated receptor-γ) has been established as a prime inducer of adipogenesis, cellular signalling factors that determine cell lineage in bone marrow remain generally unknown. Here, we show that the non-canonical Wnt pathway through CaMKII–TAK1–TAB2–NLK transcriptionally represses PPAR-γ transactivation and induces Runx2 expression, promoting osteoblastogenesis in preference to adipogenesis in bone marrow mesenchymal progenitors. Wnt-5a activates NLK (Nemo-like kinase), which in turn phosphorylates a histone methyltransferase, SETDB1 (SET domain bifurcated 1), leading to the formation of a co-repressor complex that inactivates PPAR-γ function through histone H3-K9 methylation. These findings suggest that the non-canonical Wnt signalling pathway suppresses PPAR-γ function through chromatin inactivation triggered by recruitment of a repressing histone methyltransferase, thus leading to an osteoblastic cell lineage from mesenchymal stem cells.