The transcription factor Slug represses p16Ink4a and regulates murine muscle stem cell aging
| Autor: | Yalu Zhou, Pei Zhu, Yongxing Gao, Wen Shu Wu, Furen Wu, Chunping Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Aging Cell General Physics and Astronomy 02 engineering and technology Mice Transcription (biology) Cell Self Renewal lcsh:Science Cellular Senescence Derepression Mice Knockout Multidisciplinary integumentary system biology 021001 nanoscience & nanotechnology Cell biology medicine.anatomical_structure Models Animal embryonic structures Female Stem cell 0210 nano-technology tissues Senescence animal structures Satellite Cells Skeletal Muscle Slug Science Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Muscle stem cells medicine Animals Psychological repression Transcription factor neoplasms Cyclin-Dependent Kinase Inhibitor p16 fungi General Chemistry biology.organism_classification Mice Inbred C57BL 030104 developmental biology nervous system Gene Expression Regulation lcsh:Q Snail Family Transcription Factors |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-16 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-10479-4 |
| Popis: | Activation of the p16Ink4a-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity. Here, we report that the zinc-finger transcription factor Slug is highly expressed in quiescent SCs of mice and functions as a direct transcriptional repressor of p16Ink4a. Loss of Slug promotes derepression of p16Ink4a in SCs and accelerates the entry of SCs into a fully senescent state upon damage-induced stress. p16Ink4a depletion partially rescues defects in Slug-deficient SCs. Furthermore, reduced Slug expression is accompanied by p16Ink4a accumulation in aged SCs. Slug overexpression ameliorates aged muscle regeneration by enhancing SC self-renewal through active repression of p16Ink4a transcription. Our results identify a cell-autonomous mechanism underlying functional defects of SCs at advanced age. As p16Ink4a dysregulation is the chief cause for regenerative defects of human geriatric SCs, these findings highlight Slug as a potential therapeutic target for aging-associated degenerative muscle disease. Muscle regeneration depends on self-renewal of muscle stem cells but how this is regulated on aging is unclear. Here, the authors identify Slug as regulating p16Ink4a in quiescent muscle stem cells, and when Slug expression reduces in aged stem cells, p16Ink4a accumulates, causing regenerative defects. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|