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.
Takada
Ichiro
I
Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
Mihara
Masatomo
M
Suzawa
Miyuki
M
Ohtake
Fumiaki
F
Kobayashi
Shinji
S
Igarashi
Mamoru
M
Youn
Min-Young
MY
Takeyama
Ken-ichi
K
Nakamura
Takashi
T
Mezaki
Yoshihiro
Y
Takezawa
Shinichiro
S
Yogiashi
Yoshiko
Y
Kitagawa
Hirochika
H
Yamada
Gen
G
Takada
Shinji
S
Minami
Yasuhiro
Y
Shibuya
Hiroshi
H
Matsumoto
Kunihiro
K
Kato
Shigeaki
S
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
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