Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
Celgene Quanticel Research, San Diego, CA, USA.
Cell Death Dis. 2017 Feb 23;8(2):e2631. doi: 10.1038/cddis.2017.48.
Coordination of energy metabolism is essential for homeostasis of stem cells, whereas an imbalance in energy homeostasis causes disease and accelerated aging. Here we show that deletion or enzymatic inactivation of lysine-specific demethylase 1 (Lsd1) triggers senescence in trophoblast stem cells (TSCs). Genome-wide transcriptional profiling of TSCs following Lsd1 inhibition shows gene set enrichment of aging and metabolic pathways. Consistently, global metabolomic and phenotypic analyses disclose an unbalanced redox status, decreased glutamine anaplerosis and mitochondrial function. Loss of homeostasis is caused by increased expression of sirtuin 4 (Sirt4), a Lsd1-repressed direct target gene. Accordingly, Sirt4 overexpression in wild-type TSCs recapitulates the senescence phenotype initiated by Lsd1 deletion or inhibition. Inversely, absence of Lsd1 enzymatic activity concomitant with knockdown of Sirt4 reestablishes normal glutamine anaplerosis, redox balance and mitochondrial function. In conclusion, by repression of Sirt4, Lsd1 directs the epigenetic control of TSC immortality via maintenance of metabolic flexibility.
能量代谢的协调对于干细胞的内稳态至关重要，而能量内稳态的失衡会导致疾病和加速衰老。在这里，我们表明赖氨酸特异性去甲基酶 1（Lsd1）的缺失或酶失活会触发滋养层干细胞（TSC）衰老。Lsd1 抑制后 TSC 的全基因组转录谱分析显示出衰老和代谢途径的基因集富集。一致地，全局代谢组学和表型分析揭示了不平衡的氧化还原状态、谷氨酰胺同化作用减少和线粒体功能下降。失衡是由 Sirtuin 4（Sirt4）的表达增加引起的，Sirt4 是 Lsd1 抑制的直接靶基因。因此，野生型 TSC 中 Sirt4 的过表达再现了由 Lsd1 缺失或抑制引发的衰老表型。相反，缺乏 Lsd1 酶活性伴随着 Sirt4 的敲低，可重新建立正常的谷氨酰胺同化作用、氧化还原平衡和线粒体功能。总之，通过抑制 Sirt4，Lsd1 通过维持代谢灵活性来指导 TSC 永生的表观遗传控制。
