Paul F. Glenn Center for the Biology of Aging, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305;
Paul F. Glenn Center for the Biology of Aging, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2021 Sep 14;118(37). doi: 10.1073/pnas.2025281118.
Skeletal muscle possesses remarkable regenerative ability because of the resident muscle stem cells (MuSCs). A prominent feature of quiescent MuSCs is a high content of heterochromatin. However, little is known about the mechanisms by which heterochromatin is maintained in MuSCs. By comparing gene-expression profiles from quiescent and activated MuSCs, we found that the mammalian Hairless (Hr) gene is expressed in quiescent MuSCs and rapidly down-regulated upon MuSC activation. Using a mouse model in which Hr can be specifically ablated in MuSCs, we demonstrate that Hr expression is critical for MuSC function and muscle regeneration. In MuSCs, loss of Hr results in reduced trimethylated Histone 3 Lysine 9 (H3K9me3) levels, reduced heterochromatin, increased susceptibility to genotoxic stress, and the accumulation of DNA damage. Deletion of Hr leads to an acceleration of the age-related decline in MuSC numbers. We have also demonstrated that despite the fact that Hr is homologous to a family of histone demethylases and binds to di- and trimethylated H3K9, the expression of Hr does not lead to H3K9 demethylation. In contrast, we show that the expression of Hr leads to the inhibition of the H3K9 demethylase Jmjd1a and an increase in H3K9 methylation. Taking these data together, our study has established that Hr is a H3K9 demethylase antagonist specifically expressed in quiescent MuSCs.
骨骼肌具有显著的再生能力，这要归功于其常驻的肌肉干细胞（MuSCs）。静止的 MuSCs 的一个显著特征是异染色质含量高。然而，目前对于 MuSCs 中异染色质如何维持的机制知之甚少。通过比较静止和激活的 MuSCs 的基因表达谱，我们发现哺乳动物的无毛（Hr）基因在静止的 MuSCs 中表达，并在 MuSC 激活时迅速下调。利用一种可以在 MuSCs 中特异性敲除 Hr 的小鼠模型，我们证明了 Hr 表达对于 MuSC 功能和肌肉再生至关重要。在 MuSCs 中，Hr 的缺失会导致三甲基化组蛋白 3 赖氨酸 9（H3K9me3）水平降低、异染色质减少、对遗传毒性应激的敏感性增加以及 DNA 损伤的积累。Hr 的缺失会导致 MuSC 数量随年龄增长而加速减少。我们还证明，尽管 Hr 与组蛋白去甲基酶家族同源，并与二甲基化和三甲基化的 H3K9 结合，但 Hr 的表达并不会导致 H3K9 去甲基化。相比之下，我们发现 Hr 的表达会抑制 H3K9 去甲基酶 Jmjd1a 的表达，并增加 H3K9 的甲基化。综合这些数据，我们的研究表明，Hr 是一种特异性在静止的 MuSCs 中表达的 H3K9 去甲基酶拮抗剂。
