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

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.

Pubmed ID: 17952062


  • Takada I
  • Mihara M
  • Suzawa M
  • Ohtake F
  • Kobayashi S
  • Igarashi M
  • Youn MY
  • Takeyama K
  • Nakamura T
  • Mezaki Y
  • Takezawa S
  • Yogiashi Y
  • Kitagawa H
  • Yamada G
  • Takada S
  • Minami Y
  • Shibuya H
  • Matsumoto K
  • Kato S


Nature cell biology

Publication Data

November 2, 2007

Associated Grants


Mesh Terms

  • Adipogenesis
  • Animals
  • Cells, Cultured
  • Core Binding Factor Alpha 1 Subunit
  • Down-Regulation
  • Genetic Vectors
  • Histone-Lysine N-Methyltransferase
  • Mice
  • Mice, Transgenic
  • Mutation
  • Osteogenesis
  • PPAR gamma
  • Phosphorylation
  • Plasmids
  • Signal Transduction
  • Transcriptional Activation
  • Wnt Proteins