Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle
Errα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle
复制标题
DOI：
10.1073/pnas.0401401101
复制
发表时间：
2004-04-27
影响因子：
11.1
通讯作者：
Spiegelman, BM
中科院分区：
文献类型：
--
作者：
Mootha, VK;Handschin, C;Spiegelman, BM
近期研究表明，参与氧化磷酸化（OXPHOS）的基因在糖尿病和糖尿病前期患者的骨骼肌中表达降低。此外，这些变化可能由转录辅激活因子过氧化物酶体增殖物激活受体γ辅激活因子 - 1α（PGC - 1α）介导。通过将PGC - 1α诱导的全基因组转录图谱与一种检测顺式调控元件的计算策略相结合，我们确定雌激素相关受体α（Erralpha）和GA重复结合蛋白α是调节OXPHOS途径的关键转录因子。有趣的是，编码这两种转录因子的基因本身可被PGC - 1α诱导，并且在其启动子附近包含这两种元件的变体。细胞实验证实，Erra和GA结合蛋白α在肌肉中与PGC - 1α合作，形成一个双正反馈回路，驱动许多OXPHOS基因的表达。通过使用一种Erra的合成抑制剂，我们证明了它在PGC - 1α介导的基因调控和细胞呼吸作用中的关键作用。这些结果展示了在复杂的哺乳动物系统中对基因调控网络的剖析，阐明了PGC - 1α在OXPHOS途径中的作用机制，并表明Erra激动剂可能改善2型糖尿病患者的胰岛素抵抗。
Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression in skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor alpha (Erralpha) and GA repeat-binding protein a as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1alpha-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erra and GA-binding protein a partner with PGC-1alpha a in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erra, we demonstrated its key role in PGC-1alpha-mediated effects on gene regulation and cellular respiration. These results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1alpha action in the OXPHOS pathway, and suggest that Erra agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.