Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex.
Brown fat is a specialized tissue that can dissipate energy and counteract obesity through a pattern of gene expression that greatly increases mitochondrial content and uncoupled respiration. PRDM16 is a zinc-finger protein that controls brown fat determination by stimulating brown fat-selective gene expression, while suppressing the expression of genes selective for white fat cells. To determine the mechanisms regulating this switching of gene programs, we purified native PRDM16 protein complexes from fat cells. We show here that the PRDM16 transcriptional holocompex contains C-terminal-binding protein-1 (CtBP-1) and CtBP-2, and this direct interaction selectively mediates the repression of white fat genes. This repression occurs through recruiting a PRDM16/CtBP complex onto the promoters of white fat-specific genes such as resistin, and is abolished in the genetic absence of CtBP-1 and CtBP-2. In turn, recruitment of PPAR-gamma-coactivator-1alpha (PGC-1alpha) and PGC-1beta to the PRDM16 complex displaces CtBP, allowing this complex to powerfully activate brown fat genes, such as PGC-1alpha itself. These data show that the regulated docking of the CtBP proteins on PRDM16 controls the brown and white fat-selective gene programs.
Kajimura
Shingo
S
Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
Seale
Patrick
P
Tomaru
Takuya
T
Erdjument-Bromage
Hediye
H
Cooper
Marcus P
MP
Ruas
Jorge L
JL
Chin
Sherry
S
Tempst
Paul
P
Lazar
Mitchell A
MA
Spiegelman
Bruce M
BM
D016475:3T3 Cells; D041721:3T3-L1 Cells; D002001:Adipose Tissue, Brown / Q000378:metabolism / Q000502:physiology*; D052436:Adipose Tissue, White / Q000378:metabolism / Q000502:physiology*; D000429:Alcohol Oxidoreductases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics*; D002522:Chlorocebus aethiops; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005786:Gene Expression Regulation; D005809:Genes, Regulator; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic
D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; C096794:C-terminal binding protein