Regulation of Skeletal Muscle Stem Cell Quiescence by Suv4-20h1-Dependent Facultative Heterochromatin Formation
Regulation of Skeletal Muscle Stem Cell Quiescence by Suv4-20h1-Dependent Facultative Heterochromatin Formation
复制标题
DOI：
10.1016/j.stem.2015.11.002
复制
发表时间：
2016-02-04
期刊：
影响因子：
23.9
通讯作者：
Braun, Thomas
中科院分区：
文献类型：
--
作者：
Boonsanay, Verawan;Zhang, Ting;Braun, Thomas
骨骼肌干细胞(MUSCs)是成年肌肉损伤后再生所必需的，这种反应主要需要静止MUSCs的激活。尽管需要动态调节MUSC的静止性，但人们对这一特性的决定因素知之甚少。在这里，我们证明了Suv4-20h1，一种H4K20二甲基转移酶，通过促进兼性异染色质(FHC)的形成来控制MUSC的静止。Suv4-20h1的缺失降低了FHC，并诱导了MyoD基因的转录激活和重新定位，使其远离异染色质的核周。这些作用促进了MUSC的激活，导致干细胞枯竭，损害了肌肉的长期再生。MyoD表达的遗传减少挽救了FHC的形成和失去了MUSC的静止，恢复了Suv4-20h1突变体的肌肉再生能力。综上所述，这些发现揭示了Suv4-20h1通过FHC的形成和MyoD位点的控制来积极调节MUSC的静止，从而在一生中守卫和保存干细胞库。
Skeletal muscle stem cells (MuSCs) are required for regeneration of adult muscle following injury, a response that demands activation of mainly quiescent MuSCs. Despite the need for dynamic regulation of MuSC quiescence, relatively little is known about the determinants of this property. Here, we show that Suv4-20h1, an H4K20 dimethyltransferase, controls MuSC quiescence by promoting formation of facultative heterochromatin (fHC). Deletion of Suv4-20h1 reduces fHC and induces transcriptional activation and repositioning of the MyoD locus away from the heterochromatic nuclear periphery. These effects promote MuSC activation, resulting in stem cell depletion and impaired long-term muscle regeneration. Genetic reduction of MyoD expression rescues fHC formation and lost MuSC quiescence, restoring muscle regeneration capacity in Suv4-20h1 mutants. Together, these findings reveal that Suv4-20h1 actively regulates MuSC quiescence via fHC formation and control of the MyoD locus, thereby guarding and preserving the stem cell pool over a lifetime.