A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ 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

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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-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.

Original languageEnglish
Pages (from-to)1273-1285
Number of pages13
JournalNature Cell Biology
Volume9
Issue number11
DOIs
Publication statusPublished - 2007 Nov
Externally publishedYes

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Takada, I., Mihara, M., Suzawa, M., Ohtake, F., Kobayashi, S., Igarashi, M., Youn, M. Y., Takeyama, K. I., Nakamura, T., Mezaki, Y., Takezawa, S., Yogiashi, Y., Kitagawa, H., Yamada, G., Takada, S., Minami, Y., Shibuya, H., Matsumoto, K., & Kato, S. (2007). A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ transactivation. Nature Cell Biology, 9(11), 1273-1285. https://doi.org/10.1038/ncb1647