title: A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation.
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.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Masatomo
authors.initials: M
authors.lastname: Mihara
authors.forename: Miyuki
authors.initials: M
authors.lastname: Suzawa
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ohtake
authors.forename: Shinji
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Mamoru
authors.initials: M
authors.lastname: Igarashi
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Youn
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Takeyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Mezaki
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Takezawa
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yogiashi
authors.forename: Hirochika
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
authors.forename: Shinji
authors.initials: S
authors.lastname: Takada
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shibuya
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D050156:Adipogenesis; D000818:Animals; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D015536:Down-Regulation; D005822:Genetic Vectors; D011495:Histone-Lysine N-Methyltransferase / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010012:Osteogenesis; D047495:PPAR gamma / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000071818:Wnt-5a Protein
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D047495:PPAR gamma; C493716:Runx2 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D011495:Histone-Lysine N-Methyltransferase