Li Dan, Yea Steven, Li Side, Chen Zhu, Narla Goutham, Banck Michaela, Laborda Jorge, Tan Song, Friedman Jeffrey M, Friedman Scott L, Walsh Martin J
Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.
J Biol Chem. 2005 Jul 22;280(29):26941-52. doi: 10.1074/jbc.M500463200. Epub 2005 May 25.
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.
前脂肪细胞分化发生在人类发育的不同阶段，是体重的关键决定因素。脂肪生成的转录事件不断涌现，但特定靶基因座的染色质重塑与前脂肪细胞分化之间的联系仍不清楚。我们已确定Krüppel样因子6（KLF6），一种最近描述的肿瘤抑制基因，是原癌基因Delta样1（Dlk1）的抑制因子，Dlk1是一个编码抑制脂肪细胞分化的跨膜蛋白的基因。在体内，前脂肪细胞和NIH 3T3细胞中KLF6的强制表达强烈抑制Dlk1表达，而在3T3-L1细胞中通过小干扰RNA下调KLF6可阻止脂肪生成。Dlk1的抑制需要HDAC3去乙酰化酶活性，HDAC3被招募到内源性Dlk1启动子并在那里与KLF6相互作用。我们的研究确定HDAC3与KLF6之间的相互作用是人类脂肪生成的潜在机制，并强调KLF6作为一种多功能转录调节因子的作用，它能够通过基因抑制介导脂肪细胞分化。
