SHARP1/DEC2 inhibits adipogenic differentiation by regulating the activity of C/EBP
SHARP1/DEC2 inhibits adipogenic differentiation by regulating the activity of C/EBP
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DOI：
10.1038/embor.2008.207
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发表时间：
2009-01-01
期刊：
影响因子：
7.7
通讯作者：
Taneja, Reshma
中科院分区：
文献类型：
--
作者：
Gulbagci, Neriman Tuba;Li, Li;Taneja, Reshma
SHARP 1是一种碱性螺旋-环-螺旋转录因子，在许多细胞类型中表达;然而，它调节细胞分化的机制在很大程度上仍然未知。在这里，我们表明SHARP 1负调控脂肪形成。虽然早期标记物CCAAT/增强子结合蛋白β（C/EBP β）的表达没有改变，但其关键下游靶点C/EBP α和过氧化物酶体增殖物激活受体γ（PPAR γ）被SHARP 1下调。蛋白质相互作用研究证实，SHARP 1与C/EBP β和C/EBP α相互作用并抑制其转录活性，并增强C/EBPb与组蛋白脱乙酰酶1（HDAC 1）的结合。一致地，在SHARP 1表达细胞中，HDAC 1和组蛋白甲基转移酶G9 a在分化期间保留在C/EBP α和PPAR γ 2启动子上的C/EBP调节位点，导致其表达的抑制。有趣的是，用曲格列酮处理导致HDAC 1和G9 a的置换，并挽救SHARP 1过表达细胞的分化缺陷。我们的数据表明，SHARP 1通过调节C/EBP活性来抑制脂肪形成，C/EBP活性对于脂肪形成启动子中的共阻遏物的PPAR γ配体依赖性置换是必不可少的。
SHARP1, a basic helix-loop-helix transcription factor, is expressed in many cell types; however, the mechanisms by which it regulates cellular differentiation remain largely unknown. Here, we show that SHARP1 negatively regulates adipogenesis. Although expression of the early marker CCAAT/enhancer binding protein beta (C/EBP beta) is not altered, its crucial downstream targets C/EBP alpha and peroxisome proliferator-activated receptor gamma (PPAR gamma) are downregulated by SHARP1. Protein interaction studies confirm that SHARP1 interacts with and inhibits the transcriptional activity of both C/EBP beta and C/EBP alpha, and enhances the association of C/EBPb with histone deacetylase 1 (HDAC1). Consistently, in SHARP1-expressing cells, HDAC1 and the histone methyltransferase G9a are retained at the C/EBP regulatory sites on the C/EBP alpha and PPAR gamma 2 promoters during differentiation, resulting in inhibition of their expression. Interestingly, treatment with troglitazone results in displacement of HDAC1 and G9a, and rescues the differentiation defect of SHARP1-overexpressing cells. Our data indicate that SHARP1 inhibits adipogenesis through the regulation of C/EBP activity, which is essential for PPAR gamma-ligand-dependent displacement of co-repressors from adipogenic promoters.