A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-γ transactivation
| Autor: | Yasuhiro Minami, Shinichiro Takezawa, Shinji Takada, Fumiaki Ohtake, Mamoru Igarashi, Ken-ichi Takeyama, Min Young Youn, Gen Yamada, Takashi Nakamura, Shigeaki Kato, Hirochika Kitagawa, Yoshiko Yogiashi, Yoshihiro Mezaki, Kobayashi Shinji, Miyuki Suzawa, Hiroshi Shibuya, Ichiro Takada, Masatomo Mihara, Kunihiro Matsumoto |
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| Rok vydání: | 2007 |
| Předmět: |
Transcriptional Activation
Genetic Vectors Down-Regulation Core Binding Factor Alpha 1 Subunit Mice Transgenic Wnt-5a Protein Mice Transactivation Osteogenesis Transcriptional regulation Animals Phosphorylation Cells Cultured Adipogenesis biology Wnt signaling pathway Histone-Lysine N-Methyltransferase Cell Biology Chromatin Cell biology PPAR gamma Wnt Proteins RUNX2 Histone Histone methyltransferase Mutation biology.protein Cancer research Plasmids Signal Transduction |
| Zdroj: | Nature Cell Biology. 9:1273-1285 |
| ISSN: | 1476-4679 1465-7392 |
| DOI: | 10.1038/ncb1647 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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