Krüppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1.
Preadipocyte differentiation occurs during distinct periods of human development and is a key determinant of body mass. Transcriptional events underlying adipogenesis continue to emerge, but the link between chromatin remodeling of specific target loci and preadipocyte differentiation remains elusive. We have identified Krüppel-like factor-6 (KLF6), a recently described tumor suppressor gene, as a repressor of the proto-oncogene Delta-like 1 (Dlk1), a gene encoding a transmembrane protein that inhibits adipocyte differentiation. Forced expression of KLF6 strongly inhibits Dlk1 expression in preadipocytes and NIH 3T3 cells in vivo, whereas down-regulation of KLF6 in 3T3-L1 cells by small interfering RNA prevents adipogenesis. Repression of Dlk1 requires HDAC3 deacetylase activity, which is recruited to the endogenous Dlk1 promoter where it interacts with KLF6. Our studies identify the interaction between HDAC3 and KLF6 as a potential mechanism underlying human adipogenesis, and highlight the role of KLF6 as a multifunctional transcriptional regulator capable of mediating adipocyte differentiation through gene repression.
Li
Dan
D
Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
Yea
Steven
S
Li
Side
S
Chen
Zhu
Z
Narla
Goutham
G
Banck
Michaela
M
Laborda
Jorge
J
Tan
Song
S
Friedman
Jeffrey M
JM
Friedman
Scott L
SL
Walsh
Martin J
MJ
D016475:3T3 Cells; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012097:Repressor Proteins / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D047908:Intracellular Signaling Peptides and Proteins; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D015534:Trans-Activators; D000099186:Histone Deacetylase 3; C105465:KLF6 protein, human; C000715470:MAS1 protein, human; C064045:delta protein