Kruppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1
Kruppel-like factor-6 promotes preadipocyte differentiation through histone deacetylase 3-dependent repression of DLK1
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DOI：
10.1074/jbc.m500463200
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发表时间：
2005-07-22
影响因子：
4.8
通讯作者：
Walsh, MJ
中科院分区：
文献类型：
--
作者：
Li, D;Yea, S;Walsh, MJ
前脂肪细胞分化发生在人类发育的不同时期，是体重的关键决定因素。脂肪形成背后的转录事件不断出现，但特定靶位点的染色质重塑与前脂肪细胞分化之间的联系仍然难以捉摸。我们已经确定了Kruppel-like factor-6 (KLF6)，一种最近被描述的肿瘤抑制基因，作为原癌基因Delta-like 1 （Dlk1）的抑制因子，Dlk1是一种编码抑制脂肪细胞分化的跨膜蛋白的基因。在体内，强迫表达KLF6强烈抑制Dlk1在脂肪前细胞和NIH 3T3细胞中的表达，而通过小干扰RNA下调3T3- l1细胞中的KLF6可阻止脂肪形成。Dlk1的抑制需要HDAC3去乙酰化酶活性，该活性被募集到内源性Dlk1启动子中，并与KLF6相互作用。我们的研究确定了HDAC3和KLF6之间的相互作用是人类脂肪形成的潜在机制，并强调了KLF6作为一种多功能转录调节剂的作用，能够通过基因抑制介导脂肪细胞分化。
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 Kruppel-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.