Histone Demethylase LSD1 Regulates Adipogenesis
Histone Demethylase LSD1 Regulates Adipogenesis
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DOI：
10.1074/jbc.m110.151209
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发表时间：
2010-09-24
影响因子：
4.8
通讯作者：
Parrizas, Marcelina
中科院分区：
文献类型：
--
作者：
Musri, Melina M.;Carmona, Mari Carmen;Parrizas, Marcelina
表观遗传机制，特别是组蛋白的酶修饰，是细胞分化的关键因素，这是一个受调节的过程，它允许前体细胞基本上变成不同的细胞类型，同时保持相同的遗传设备。我们之前已经描述过，脂肪形成基因的启动子在脂肪前细胞组蛋白H3 （H3K4）的Lys(4)上显示出显著水平的二甲基化，在那里这些基因仍然是沉默的，从而维持前体细胞的染色质处于接受状态。在这里，我们发现几种组蛋白去甲基化酶和甲基转移酶的表达在脂肪形成过程中增加，表明这些蛋白在这一过程中起重要作用。H3K4/K9去甲基化酶LSD1的敲低导致3T3-L1前脂肪细胞的分化明显降低。这一结果与转录因子cebpa启动子的H3K4二甲基化减少和H3K9二甲基化增加有关，cebpa的表达在刺激分化时必须被诱导200倍。因此，我们的数据表明LSD1通过反对H3K9甲基转移酶的作用来维持该启动子中染色质的允许状态。敲低H3K9甲基转移酶SETDB1产生相反的结果，通过降低H3K9二甲基化和增加cebpa启动子上的H3K4二甲基化水平，有利于分化。这些发现表明，脂肪形成基因的组蛋白甲基化状态以及参与其维持的蛋白质的表达和功能在脂肪形成中起着至关重要的作用。
Epigenetic mechanisms, in particular the enzymatic modification of histones, are a crucial element of cell differentiation, a regulated process that allows a precursor cell basically to turn into a different cell type while maintaining the same genetic equipment. We have previously described that the promoters of adipogenic genes display significant levels of dimethylation at the Lys(4) of histone H3 (H3K4) in preadipocytes, where these genes are still silenced, thus maintaining the chromatin of the precursor cell in a receptive state. Here, we show that the expression of several histone demethylases and methyltransferases increases during adipogenesis, suggesting an important role for these proteins in this process. Knockdown of the H3K4/K9 demethylase LSD1 results in markedly decreased differentiation of 3T3-L1 preadipocytes. This outcome is associated with decreased H3K4 dimethylation and increased H3K9 dimethylation at the promoter of transcription factor cebpa, whose expression must be induced > 200-fold upon stimulation of differentiation. Thus, our data suggest that LSD1 acts to maintain a permissive state of the chromatin in this promoter by opposing the action of a H3K9 methyltransferase. Knockdown of H3K9 methyltransferase SETDB1 produced the opposite results, by decreasing H3K9 dimethylation and increasing H3K4 dimethylation levels at the cebpa promoter and favoring differentiation. These findings indicate that the histone methylation status of adipogenic genes as well as the expression and function of the proteins involved in its maintenance play a crucial role in adipogenesis.