Uhrf1 governs the proliferation and differentiation of muscle satellite cells
Hiroshi Sakai,
Yuichiro Sawada,
Naohito Tokunaga,
Kaori Tanaka,
So Nakagawa,
Iori Sakakibara,
Yusuke Ono,
So-ichiro Fukada,
Yasuyuki Ohkawa,
Tadahiko Kikugawa,
Takashi Saika,
Yuuki Imai
Affiliations
Hiroshi Sakai
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; Corresponding author
Yuichiro Sawada
Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
Naohito Tokunaga
Division of Analytical Bio-Medicine, Advanced Research Support Center, Ehime University, Toon, Ehime 791-0295, Japan
Kaori Tanaka
Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-0054, Japan
So Nakagawa
Department of Molecular Life Science, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan
Iori Sakakibara
Department of Nutritional Physiology, Institute of Medical Nutrition, Tokushima University Graduate School, Kuramoto-cho, Tokushima 770-8503, Japan
Yusuke Ono
Department of Muscle Development and Regeneration, Institute of Molecular Embryology and Genetics, Kumamoto University, Honjo, Kumamoto 860-0811, Japan
So-ichiro Fukada
Project for Muscle Stem Cell Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan
Yasuyuki Ohkawa
Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-0054, Japan
Tadahiko Kikugawa
Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
Takashi Saika
Department of Urology, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
Yuuki Imai
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; Corresponding author
Summary: 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. Uhrf1-deficient myogenic cells exhibited aberrant upregulation of transcripts, including Sox9, 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.
