Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency.
Stat3 promotes mitochondrial transcription and oxidative respiration during maintenance and induction of naive pluripotency.
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DOI：
10.15252/embj.201592629
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Martello G
中科院分区：
文献类型：
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作者：
Carbognin E;Betto RM;Soriano ME;Smith AG;Martello G
转录因子STAT3指导细胞因子白血病抑制因子(LIF)下游多能小鼠胚胎干细胞(ES细胞)的自我更新。STAT3上调ES细胞基因调控网络中的关键转录因子，以维持幼稚的同一性。STAT3也有助于ES细胞的快速增殖。在这里，我们表明，STAT3增加了线粒体编码的转录本的表达，并增强了氧化代谢。染色质免疫沉淀显示，STAT3与线粒体基因组结合，与直接转录调控一致。一种主要定位于线粒体的STAT3工程化形式足以支持促进ES细胞的增殖，但不足以维持其未分化的表型。此外，在从启动状态到多潜能的幼稚状态的重新编程过程中，STAT3类似地上调线粒体转录并促进代谢重置。这些发现表明，LIF/STAT3对幼稚多能性的有效刺激归因于线粒体呼吸和核转录因子的平行和协同诱导。
Transcription factor Stat3 directs self‐renewal of pluripotent mouse embryonic stem (ES) cells downstream of the cytokine leukemia inhibitory factor (LIF). Stat3 upregulates pivotal transcription factors in the ES cell gene regulatory network to sustain naïve identity. Stat3 also contributes to the rapid proliferation of ES cells. Here, we show that Stat3 increases the expression of mitochondrial‐encoded transcripts and enhances oxidative metabolism. Chromatin immunoprecipitation reveals that Stat3 binds to the mitochondrial genome, consistent with direct transcriptional regulation. An engineered form of Stat3 that localizes predominantly to mitochondria is sufficient to support enhanced proliferation of ES cells, but not to maintain their undifferentiated phenotype. Furthermore, during reprogramming from primed to naïve states of pluripotency, Stat3 similarly upregulates mitochondrial transcripts and facilitates metabolic resetting. These findings suggest that the potent stimulation of naïve pluripotency by LIF/Stat3 is attributable to parallel and synergistic induction of both mitochondrial respiration and nuclear transcription factors.