COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis.
Wnt signaling through beta-catenin and TCF maintains preadipocytes in an un-differentiated proliferative state; however, the molecular pathway has not been completely defined. By integrating gene expression microarray, chromatin immunoprecipitation-chip, and cell-based experimental approaches, we show that Wnt/beta-catenin signaling activates the expression of COUP-TFII which recruits the SMRT corepressor complex to the first introns located downstream from the first exons of both PPARgamma1 and gamma2 mRNAs. This maintains the local chromatin in a hypoacetylated state and represses PPARgamma gene expression to inhibit adipogenesis. Our experiments define the COUP-TFII/SMRT complex as a previously unappreciated component of the linear pathway that directly links Wnt/beta-catenin signaling to repression of PPARgamma gene expression and the inhibition of adipogenesis.
Okamura
Masashi
M
Laboratory of Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
Kudo
Hiromi
H
Wakabayashi
Ken-ichi
K
Tanaka
Toshiya
T
Nonaka
Aya
A
Uchida
Aoi
A
Tsutsumi
Shuichi
S
Sakakibara
Iori
I
Naito
Makoto
M
Osborne
Timothy F
TF
Hamakubo
Takao
T
Ito
Sadayoshi
S
Aburatani
Hiroyuki
H
Yanagisawa
Masashi
M
Kodama
Tatsuhiko
T
Sakai
Juro
J
D000107:Acetylation; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D051838:COUP Transcription Factor I / Q000235:genetics / Q000502:physiology*; D002843:Chromatin; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D051379:Mice; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D051838:COUP Transcription Factor I; D002843:Chromatin; D004268:DNA-Binding Proteins; C539131:Ncor2 protein, mouse; C539132:Ncor2 protein, rat; D056985:Nuclear Receptor Co-Repressor 2; D047495:PPAR gamma; D012333:RNA, Messenger; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin