Targeted disruption of the basic Krüppel-like factor gene (Klf3) reveals a role in adipogenesis.
Krüppel-like factors (KLFs) recognize CACCC and GC-rich sequences in gene regulatory elements. Here, we describe the disruption of the murine basic Krüppel-like factor gene (Bklf or Klf3). Klf3 knockout mice have less white adipose tissue, and their fat pads contain smaller and fewer cells. Adipocyte differentiation is altered in murine embryonic fibroblasts from Klf3 knockouts. Klf3 expression was studied in the 3T3-L1 cellular system. Adipocyte differentiation is accompanied by a decline in Klf3 expression, and forced overexpression of Klf3 blocks 3T3-L1 differentiation. Klf3 represses transcription by recruiting C-terminal binding protein (CtBP) corepressors. CtBPs bind NADH and may function as metabolic sensors. A Klf3 mutant that does not bind CtBP cannot block adipogenesis. Other KLFs, Klf2, Klf5, and Klf15, also regulate adipogenesis, and functional CACCC elements occur in key adipogenic genes, including in the C/ebpalpha promoter. We find that C/ebpalpha is derepressed in Klf3 and Ctbp knockout fibroblasts and adipocytes from Klf3 knockout mice. Chromatin immunoprecipitations confirm that Klf3 binds the C/ebpalpha promoter in vivo. These results implicate Klf3 and CtBP in controlling adipogenesis.
Sue
Nancy
N
School of Molecular and Microbial Biosciences, G08, University of Sydney, Sydney, NSW 2006, Australia.
Jack
Briony H A
BH
Eaton
Sally A
SA
Pearson
Richard C M
RC
Funnell
Alister P W
AP
Turner
Jeremy
J
Czolij
Robert
R
Denyer
Gareth
G
Bao
Shisan
S
Molero-Navajas
Juan Carlos
JC
Perkins
Andrew
A
Fujiwara
Yuko
Y
Orkin
Stuart H
SH
Bell-Anderson
Kim
K
Crossley
Merlin
M
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000273:Adipose Tissue / Q000196:embryology / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008957:Models, Genetic; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*
D004268:DNA-Binding Proteins; C529780:Klf3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein