Oberti Daniele, Biasini Adriano, Kirschmann Moritz Alexander, Genoud Christel, Stunnenberg Rieka, Shimada Yukiko, Bühler Marc
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, Petersplatz 10, 4003 Basel, Switzerland.
Cell Rep. 2015 Jan 6;10(1):47-61. doi: 10.1016/j.celrep.2014.12.006. Epub 2014 Dec 24.
Epigenetic mechanisms can be influenced by environmental cues and thus evoke phenotypic variation. This plasticity can be advantageous for adaptation but also detrimental if not tightly controlled. Although having attracted considerable interest, it remains largely unknown if and how environmental cues such as temperature trigger epigenetic alterations. Using fission yeast, we demonstrate that environmentally induced discontinuous phenotypic variation is buffered by a negative feedback loop that involves the RNase Dicer and the protein disaggregase Hsp104. In the absence of Hsp104, Dicer accumulates in cytoplasmic inclusions and heterochromatin becomes unstable at elevated temperatures, an epigenetic state inherited for many cell divisions after the heat stress. Loss of Dicer leads to toxic aggregation of an exogenous prionogenic protein. Our results highlight the importance of feedback regulation in building epigenetic memory and uncover Hsp104 and Dicer as homeostatic controllers that buffer environmentally induced stochastic epigenetic variation and toxic aggregation of prionogenic proteins.
表观遗传机制可受环境线索影响，从而引发表型变异。这种可塑性对适应可能有利，但如果控制不当也会有害。尽管已引起相当大的关注，但温度等环境线索是否以及如何触发表观遗传改变在很大程度上仍不清楚。利用裂殖酵母，我们证明环境诱导的不连续表型变异由一个负反馈环缓冲，该负反馈环涉及核糖核酸酶Dicer和蛋白质解聚酶Hsp104。在没有Hsp104的情况下，Dicer在细胞质内含物中积累，并且异染色质在高温下变得不稳定，这种表观遗传状态在热应激后会在许多细胞分裂中遗传。Dicer的缺失会导致外源性朊病毒原性蛋白的毒性聚集。我们的结果突出了反馈调节在建立表观遗传记忆中的重要性，并揭示了Hsp104和Dicer作为稳态控制器，可缓冲环境诱导的随机表观遗传变异和朊病毒原性蛋白的毒性聚集。
