Sakai Hiroshi, Sawada Yuichiro, Tokunaga Naohito, Tanaka Kaori, Nakagawa So, Sakakibara Iori, Ono Yusuke, Fukada So-Ichiro, Ohkawa Yasuyuki, Kikugawa Tadahiko, Saika Takashi, Imai Yuuki
Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University, Toon, Ehime 791-0295, Japan.
Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan.
iScience. 2022 Feb 14;25(3):103928. doi: 10.1016/j.isci.2022.103928. eCollection 2022 Mar 18.
DNA methylation is an essential form of epigenetic regulation responsible for cellular identity. In muscle stem cells, termed satellite cells, DNA methylation patterns are tightly regulated during differentiation. However, it is unclear how these DNA methylation patterns affect the function of satellite cells. We demonstrate that a key epigenetic regulator, ubiquitin like with PHD and RING finger domains 1 (Uhrf1), is activated in proliferating myogenic cells but not expressed in quiescent satellite cells or differentiated myogenic cells in mice. Ablation of Uhrf1 in mouse satellite cells impairs their proliferation and differentiation, leading to failed muscle regeneration. -deficient myogenic cells exhibited aberrant upregulation of transcripts, including , with the reduction of DNA methylation level of their promoter and enhancer region. These findings show that Uhrf1 is a critical epigenetic regulator of proliferation and differentiation in satellite cells, by controlling cell-type-specific gene expression via maintenance of DNA methylation.
DNA甲基化是负责细胞特性的表观遗传调控的一种重要形式。在被称为卫星细胞的肌肉干细胞中，DNA甲基化模式在分化过程中受到严格调控。然而，尚不清楚这些DNA甲基化模式如何影响卫星细胞的功能。我们证明，一种关键的表观遗传调节因子，即具有PHD和RING指结构域的泛素样蛋白1（Uhrf1），在增殖的成肌细胞中被激活，但在小鼠静止卫星细胞或分化的成肌细胞中不表达。在小鼠卫星细胞中敲除Uhrf1会损害其增殖和分化，导致肌肉再生失败。Uhrf1缺陷的成肌细胞表现出转录本的异常上调，包括，其启动子和增强子区域的DNA甲基化水平降低。这些发现表明，Uhrf1是卫星细胞增殖和分化的关键表观遗传调节因子，通过维持DNA甲基化来控制细胞类型特异性基因表达。
