Ryan_Browlie_Whyard-Stress_Hsp90_Transposon

Abstract: Background: Transposable elements (TEs) have been recognized as potentially powerful drivers of genomic evolutionary change, but factors affecting their mobility and regulation remain poorly understood. Chaperones such as Hsp90 buffer environmental perturbations by regulating protein conformation, but are also part of the PIWI-interacting RNA pathway, which regulates genomic instability arising from mobile TEs in the germline. Stress-induced mutagenesis from TE movement could thus arise from functional trade-offs in the dual roles of Hsp90. Results: We examined the functional constraints of Hsp90 and its role as a regulator of TE mobility by exposing nematodes (Caenorhabditis elegans and C. briggsae) to environmental stressors, with and without RNAi-induced silencing of Hsp90. TE excision rates increased with environmental stress intensity at multiple loci in several strains of each species. These effects were compounded by RNAi-induced knockdown of Hsp90. Mutation frequencies at the unc-22 marker gene in the offspring of exposed animals mirrored the effects of our environmental stressors and RNAi-induced silencing of Hsp90. Conclusions: Our results support a role for Hsp90 in the suppression of TE mobility, and demonstrate that that these regulatory mechanisms can be overwhelmed with moderate environmental stressors. By affecting genomic stability in germline cells, stress-induced mutations arising from TE mobility and insertions affect the phenotype and genotype of subsequent generations. These findings have important implications for understanding stress-induced mutagenesis and genome evolutionary change.

摘要：
背景：转座因子（Transposable elements, TEs）已被证实为基因组进化改变的潜在强效驱动因子，但目前学界对影响其转座活性与调控机制的相关因素仍知之甚少。诸如热休克蛋白90（Hsp90）这类分子伴侣可通过调控蛋白质构象缓冲环境扰动，同时亦是PIWI互作RNA通路（PIWI-interacting RNA pathway）的组成部分；该通路可在生殖细胞中调控由可移动转座因子引发的基因组不稳定性。因此，由转座因子转座引发的应激诱导诱变，可能源于Hsp90双重功能之间的功能权衡。
结果：本研究通过将两种线虫——秀丽隐杆线虫（Caenorhabditis elegans）与布氏隐杆线虫（C. briggsae）——分别暴露于环境胁迫条件下，并辅以或不辅以RNA干扰（RNA interference, RNAi）介导的Hsp90基因沉默，探究了Hsp90的功能限制及其作为转座因子转座调控因子的作用。在两个物种的多个菌株中，多个基因座的转座因子切出率均随环境胁迫强度升高而上升。RNA干扰介导的Hsp90基因敲低进一步加剧了上述效应。暴露组动物后代中unc-22标记基因的突变频率，与环境胁迫及Hsp90的RNAi沉默所产生的效应完全一致。
结论：本研究结果证实Hsp90可抑制转座因子的转座活性，并表明中等强度的环境胁迫即可突破这类调控机制。由转座因子转座与插入引发的应激诱导突变，可通过影响生殖细胞的基因组稳定性，进而改变后代的表型与基因型。本研究结果对于理解应激诱导诱变与基因组进化改变具有重要的理论意义。