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

Nature Cell Biology volume 9, pages 1273–1285 (2007)Cite this article

A Retraction to this article was published on 31 October 2014

A Corrigendum to this article was published on 30 November 2012

This article has been updated

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.

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Figure 1: Wnt-5a signalling suppresses the transactivation function of PPAR-γ through CaMKII−TAK1−TAB2−NLK.
Figure 2: Wnt-5a inhibits adipogenesis and induces osteoblastogenesis in bone marrow mesenchymal stem cells.
Figure 3: Bone analysis of distal femora of 18-weeks-old WT, Wnt-5a+/−, Wnt-3a+/− and PPAR-γ+/− male mice.
Figure 4: SETDB1 and CHD7 form a complex with PPAR-γ and NLK in a Wnt-5a-dependent manner.
Figure 5: Phosphorylated SETDB1 forms a complex with CHD7–NLK–PPAR-γ.
Figure 6: Wnt-5a-dependent recruitment of NLK containing corepressor complex.
Figure 7: NLK, SETDB1 and CHD7 RNAi abrogated Wnt-5a-dependent differentiation and recruitment of modified H3.

Change history

  • 30 November 2012

    Nat. Cell Biol. 9, 1273–1285 (2007); published online 21st October 2007 In the version of this Article initially published, Figs 6a and 6c contained panels that were inadvertently duplicated. In Fig. 6a, the panels in the right-hand column (Distal) corresponding to αSETDB1, αCHD7 and αNLK were duplicated.

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Acknowledgements

We thank A. P. Kouzmenko, M. Kim and R. Fujiki for helpful discussions and H. Higuchi and S. Fujiyama for manuscript preparation. And we also thank S. Ishii (RIKEN Tsukuba Institute) for helpful advice and T. Komori (Nagasaki University) for the kind gift of the Runx2 expression vector and reporter vector. This work was supported, in part, by a Grant-In-Aid for Basic Research Activities for Innovative Biosciences (BRAIN) and Priority Areas from the Ministry of Education, Science, Sports, and Culture of Japan (to S.K.).

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Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, 113-0032, Tokyo, Japan

    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 & Shigeaki Kato

  2. ERATO, Japan Science and Technology, Honcho 4-1-8, Kawaguchi, 332-0012, Saitama, Japan

    Fumiaki Ohtake, Shinji Kobayashi, Takashi Nakamura & Shigeaki Kato

  3. Department of Medicine and Bioregulatory Sciences, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-3, 770-8503, Tokushima, Japan

    Masatomo Mihara

  4. Center for Animal Resources and Development (CARD), Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Honjo 2-2-1, Kumamoto, 860-0811, Japan

    Gen Yamada

  5. Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki, 444-8787, Aichi, Japan

    Shinji Takada

  6. Department of Genome Sciences, Graduate School of Medicine, Kobe University, 650-0017, Kobe, Japan

    Yasuhiro Minami

  7. Department of Molecular Cell Biology, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, and CREST, JST, Kanda-Surugadai, Chiyoda-kuM, 101-0062, Tokyo, Japan

    Hiroshi Shibuya

  8. Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, 464-8602, Nagoya, Japan

    Kunihiro Matsumoto

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Takada, I., Mihara, M., Suzawa, M. et al. A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ transactivation. Nat Cell Biol 9, 1273–1285 (2007). https://doi.org/10.1038/ncb1647

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