Tosic Milica, Allen Anita, Willmann Dominica, Lepper Christoph, Kim Johnny, Duteil Delphine, Schüle Roland
Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-University Freiburg, Breisacherstrasse 66, 79106, Freiburg, Germany.
Department of Embryology, Carnegie Institution, 3520 San Martin Drive, Baltimore, MD, 21218, USA.
Nat Commun. 2018 Jan 25;9(1):366. doi: 10.1038/s41467-017-02740-5.
Satellite cells are muscle stem cells required for muscle regeneration upon damage. Of note, satellite cells are bipotent and have the capacity to differentiate not only into skeletal myocytes, but also into brown adipocytes. Epigenetic mechanisms regulating fate decision and differentiation of satellite cells during muscle regeneration are not yet fully understood. Here, we show that elevated levels of lysine-specific demethylase 1 (Kdm1a, also known as Lsd1) have a beneficial effect on muscle regeneration and recovery after injury, since Lsd1 directly regulates key myogenic transcription factor genes. Importantly, selective Lsd1 ablation or inhibition in Pax7-positive satellite cells, not only delays muscle regeneration, but changes cell fate towards brown adipocytes. Lsd1 prevents brown adipocyte differentiation of satellite cells by repressing expression of the novel pro-adipogenic transcription factor Glis1. Together, downregulation of Glis1 and upregulation of the muscle-specific transcription program ensure physiological muscle regeneration.
卫星细胞是肌肉损伤后肌肉再生所需的肌肉干细胞。值得注意的是，卫星细胞具有双向分化能力，不仅能够分化为骨骼肌细胞，还能分化为棕色脂肪细胞。目前，肌肉再生过程中调节卫星细胞命运决定和分化的表观遗传机制尚未完全明确。在此，我们发现赖氨酸特异性去甲基化酶1（Kdm1a，也称为Lsd1）水平升高对损伤后的肌肉再生和恢复具有有益作用，因为Lsd1直接调控关键的生肌转录因子基因。重要的是，在Pax7阳性卫星细胞中选择性敲除或抑制Lsd1，不仅会延迟肌肉再生，还会使细胞命运向棕色脂肪细胞转变。Lsd1通过抑制新型促脂肪生成转录因子Glis1的表达来阻止卫星细胞向棕色脂肪细胞分化。总之，Glis1的下调和肌肉特异性转录程序的上调确保了生理性肌肉再生。
