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J. Biol. Chem., Vol. 280, Issue 29, 26941-26952, July 22, 2005

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Krüppel-like Factor-6 Promotes Preadipocyte Differentiation through Histone Deacetylase 3-dependent Repression of DLK1^*

From the ^aDivision of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, the ^eDepartment of Inorganic and Organic Chemistry and Biochemistry, Molecular Biology Branch, Medical School, University of Castilla-La Mancha, 02071 Albacete, Spain, the ^cDepartment of Pediatrics, Mount Sinai School of Medicine, New York, New York 10029, ^dHoward Hughes Medical Institute, Laboratory of Molecular Genetics, Rockefeller University, New York, New York 10021, and the ^fCenter for Gene Regulation, the Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802

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.

Received for publication, January 13, 2005 , and in revised form, May 9, 2005.

^* This work was supported in part by United States Public Health Service Awards DK37340 (to S. L. F.), DK56621 (to S. L. F.), HL67099 (to M. J. W.), CA98552 (to M. J. W.), and DK41096 (to J. M. F.) from the National Institutes of Health and Department of Defense Grant DAMD 17-03-01-0100 (to S. L. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b Performed this work as a Medical Student Research Fellow of the Howard Hughes Medical Institute.

^g Pew Scholar in the Biomedical Sciences.

^h To whom correspondence may be addressed: Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave., Rm. 11-70C, New York, NY 10029. Tel.: 212-659-9501; Fax: 212-849-2574; E-mail: scott.friedman{at}mssm.edu.

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