表观遗传应激反应通过Hoxa9发育信号诱导肌肉干细胞衰老
Simon Schwörer1, Friedrich Becker1, Christian Feller2
1Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.
Nature
|December 6, 2016
概括
衰老会通过表观遗传变化损害肌肉干细胞的功能. 在老化的细胞中异常激活Hoxa9驱动发育途径,抑制再生,但向Hoxa9可以恢复功能.
科学领域:
- 表观遗传学
- 干细胞生物学
- 老龄化研究
背景情况:
- 干细胞功能随着年龄的增长而下降,影响组织再生.
- 发育途径的改变与与年龄相关的干细胞功能障碍有关.
- 霍克斯基因在干细胞衰老中的作用在很大程度上是未知的.
研究的目的:
- 研究衰老肌肉干细胞 (卫星细胞) 的表观遗传应激反应.
- 确定霍克斯基因,特别是霍克斯9在与年龄相关的干细胞衰退中的作用.
- 确定Hoxa9影响卫星细胞功能和肌肉再生的机制.
主要方法:
- 年轻小鼠和老鼠卫星细胞的表观遗传应激反应比较.
- 在激活的卫星细胞中分析染色体标记和Hox基因表达 (特别是HoxA9).
- 涉及抑制异常染色体激活或HoxA9删除/过度表达的干预研究.
- 对应干预的卫星细胞功能和肌肉再生能力的评估.
主要成果:
- 老鼠在激活的卫星细胞中表现出改变的表观遗传应激反应,并产生异常的活性染色体标记.
- 在老化的卫星细胞中,这种变化导致Hoxa9的诱导,而不是其他Hox基因.
- 已知可抑制卫星细胞功能的多种发育途径 (Wnt,TGFβ,JAK/ STAT,衰老信号) 被激活.
- 抑制异常染色体激活或删除Hoxa9改善了老鼠的肌肉再生.
- 在年轻的卫星细胞中过度表达Hoxa9模仿了与衰老相关的缺陷,这些缺陷通过抑制Hoxa9向途径而可逆.
结论:
- 标志着Hoxa9诱导的老化卫星细胞的表观遗传应激反应限制了肌肉干细胞的功能和再生.
- Hoxa9作为一个关键的调解者,重新激活抑制老化肌肉中的卫星细胞活动的发育途径.
- 针对Hoxa9或其下游途径为改善老年人肌肉再生提供了潜在的治疗策略.
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