SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-γ Co-activator-1α (PGC-1α) Gene in Skeletal Muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD
SIRT1 Controls the Transcription of the Peroxisome Proliferator-activated Receptor-γ Co-activator-1α (PGC-1α) Gene in Skeletal Muscle through the PGC-1α Autoregulatory Loop and Interaction with MyoD
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DOI：
10.1074/jbc.m109.022749
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发表时间：
2009-08-14
影响因子：
4.8
通讯作者：
Villarroya, Francesc
中科院分区：
文献类型：
--
作者：
Amat, Ramon;Planavila, Anna;Villarroya, Francesc
过氧化物酶体增殖体激活受体- γ共激活因子-1 α (PGC-1 α)是一种转录共激活因子，可协调调节不同组织中代谢相关基因的表达。在这里，我们发现缺乏sirtuin家族去乙酰化酶SIRT1的小鼠骨骼肌中PGC-1 α的表达减少。相反，分化的C2C12肌管中SIRT1的激活或过表达增加了PGC-1 α mRNA的表达。SIRT1的转录促进作用通过刺激PGC-1 α启动子活性发生，并通过肌细胞增强因子2 (MEF2)，特别是肌生成决定因子（MyoD）的共同转染而增强。SIRT1与PGC-1 α基因的近端启动子区域结合，MEF2C或MyoD也与该区域相互作用，从而增强了这种相互作用。在MyoD存在的情况下，SIRT1促进了PGC-1 α阳性的自调节表达环，因此在MyoD和SIRT1共表达的情况下，PGC-1 α的过表达增加了PGC-1 α启动子的活性。染色质免疫沉淀显示SIRT1与PGC-1 α启动子相互作用，增加PGC-1 α向其自身启动子区域的募集。免疫沉淀实验进一步表明，MyoD增强了SIRT1-PGC-1 α的相互作用。总的来说，这些数据表明SIRT1控制骨骼肌中PGC-1 α基因的表达，MyoD是这一作用的关键中介。MyoD参与SIRT1依赖性PGC-1 α表达可能有助于解释SIRT1驱动肌肉特异性基因表达和代谢的能力。PGC-1 α基因转录的自调节控制似乎是骨骼肌中SIRT1转录激活反应的关键机制。
Peroxisome proliferator activated receptor-gamma co-activator-1 alpha (PGC-1 alpha) is a transcriptional co-activator that coordinately regulates the expression of distinct sets of metabolism-related genes in different tissues. Here we show that PGC-1 alpha expression is reduced in skeletal muscles from mice lacking the sirtuin family deacetylase SIRT1. Conversely, SIRT1 activation or overexpression in differentiated C2C12 myotubes increased PGC-1 alpha mRNA expression. The transcription-promoting effects of SIRT1 occurred through stimulation of PGC-1 alpha promoter activity and were enhanced by co-transfection of myogenic factors, such as myocyte enhancer factor 2 (MEF2) and, especially, myogenic determining factor (MyoD). SIRT1 bound to the proximal promoter region of the PGC-1 alpha gene, an interaction potentiated by MEF2C or MyoD, which also interact with this region. In the presence of MyoD, SIRT1 promoted a positive autoregulatory PGC-1 alpha expression loop, such that overexpression of PGC-1 alpha increased PGC-1 alpha promoter activity in the presence of co-expressed MyoD and SIRT1. Chromatin immunoprecipitation showed that SIRT1 interacts with PGC-1 alpha promoter and increases PGC-1 alpha recruitment to its own promoter region. Immunoprecipitation assays further showed that SIRT1-PGC-1 alpha interactions are enhanced by MyoD. Collectively, these data indicate that SIRT1 controls PGC-1 alpha gene expression in skeletal muscle and that MyoD is a key mediator of this action. The involvement of MyoD in SIRT1-dependent PGC-1 alpha expression may help to explain the ability of SIRT1 to drive muscle-specific gene expression and metabolism. Autoregulatory control of PGC-1 alpha gene transcription seems to be a pivotal mechanism for conferring a transcription-activating response to SIRT1 in skeletal muscle.