Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60
Early adipogenesis is regulated through USP7-mediated deubiquitination of the histone acetyltransferase TIP60
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DOI：
10.1038/ncomms3656
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发表时间：
2013-10-01
影响因子：
16.6
通讯作者：
Kalkhoven, Eric
中科院分区：
文献类型：
--
作者：
Gao, Yuan;Koppen, Arjen;Kalkhoven, Eric
包括乙酰转移酶Tip 60在内的转录辅助调节因子在复杂的细胞过程如分化中起关键作用。虽然翻译后修饰已成为一个重要的机制，以调节转录辅因子的活性，识别相应的去修饰酶仍然难以捉摸。在这里，我们表明，Tip 60蛋白的表达，这是必不可少的脂肪细胞分化，是通过多个残基上的多聚泛素化调节。USP 7是3 T3-L1脂肪细胞和小鼠脂肪组织中的一种显性去泛素化酶，在完整细胞和体外均可使Tip 60去泛素化，并增加Tip 60蛋白水平。此外，USP 7表达和活性的抑制会减少脂肪形成。转录组分析揭示了Tip 60和USP 7共同调控的几个细胞周期基因。任何一个因子的敲低都会导致有丝分裂克隆扩增受损，这是脂肪形成的早期步骤。这些结果揭示了去泛素化的转录辅调节是一个关键的机制，在早期脂肪形成的调节。
Transcriptional coregulators, including the acetyltransferase Tip60, have a key role in complex cellular processes such as differentiation. Whereas post-translational modifications have emerged as an important mechanism to regulate transcriptional coregulator activity, the identification of the corresponding demodifying enzymes has remained elusive. Here we show that the expression of the Tip60 protein, which is essential for adipocyte differentiation, is regulated through polyubiquitination on multiple residues. USP7, a dominant deubiquitinating enzyme in 3T3-L1 adipocytes and mouse adipose tissue, deubiquitinates Tip60 both in intact cells and in vitro and increases Tip60 protein levels. Furthermore, inhibition of USP7 expression and activity decreases adipogenesis. Transcriptome analysis reveals several cell cycle genes to be co-regulated by both Tip60 and USP7. Knockdown of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis.