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- Title
A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation.
- Authors
Takada, Ichiro; Mihara, Masatomo; Suzawa, Miyuki; Ohtake, Fumiaki; Kobayashi, Shinji; Igarashi, Mamoru; Youn, Min-Young; Takeyama, Ken-ichi; Nakamura, Takashi; Mezaki, Yoshihiro; Takezawa, Shinichiro; Yogiashi, Yoshiko; Kitagawa, Hirochika; Yamada, Gen; Takada, Shinji; Minami, Yasuhiro; Shibuya, Hiroshi; Matsumoto, Kunihiro; Kato, Shigeaki
- Abstract
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-gamma (peroxisome proliferator activated receptor-gamma) 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-gamma 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-gamma function through histone H3-K9 methylation. These findings suggest that the non-canonical Wnt signalling pathway suppresses PPAR-gamma function through chromatin inactivation triggered by recruitment of a repressing histone methyltransferase, thus leading to an osteoblastic cell lineage from mesenchymal stem cells.
- Publication
Nature cell biology, 2007, Vol 9, Issue 11, p1273
- ISSN
1465-7392
- Publication type
Journal Article
- DOI
10.1038/ncb1647