Transposable elements function as mechanical sensors [HiCAR]

Transposable elements (TEs), comprising almost half of the genome, are tightly controlled by intrinsic factors. However, how TEs are modulated by extrinsic mechanical forces remains unknown. To address this question, we culture human embryonic stem cells on hydrogels with different rigidity and comprehensively analyze the changes in transcriptome, epigenome and genome architecture of TEs, and find that TEs are able to sense mechanical forces. Upon sensing changes in substrate rigidity, a majority of TEs exhibit elevated or declined transcription, accompanied by corresponding chromatin state alterations. Moreover, mechanotransducer YAP binds directly to a subset of TEs, especially LTR7/HERV-H, and its loss partly recapitulates effects of soft substrate on TEs. Notably, mechanical forces are required for TEs' chromatin interaction through YAP and CTCF cooperation. Functionally, mechano-sensing TE-enhancer directs definitive endoderm formation through the regulation of distal target, FAM189A2. Overall, our results demonstrate that TEs are mechanical sensors, and that TE-enhancers dictate cell fate. Overall design: Cells were cultured on the hydrogels with different rigidity, and were collected for RNA-seq, ChIP-seq and HiCAR.

转座元件（Transposable Elements, TEs）约占基因组序列的一半，其活性受到内在因子的严密调控。然而，外在机械力如何调控转座元件的活性，目前仍未明确。为解答这一科学问题，本研究将人类胚胎干细胞接种于不同刚度的水凝胶基质上培养，并全面分析转座元件的转录组、表观基因组及基因组三维结构变化，发现转座元件可感知机械力信号。当感知到基质刚度变化时，绝大多数转座元件的转录水平出现上调或下调，并伴随相应的染色质状态改变。此外，机械转导因子YAP可直接结合部分转座元件，尤其是LTR7/HERV-H亚型；敲除YAP可部分重现软基质对转座元件的调控效应。值得注意的是，转座元件的染色质相互作用依赖于机械力通过YAP与CTCF的协同作用实现。功能层面上，感知机械力的转座元件增强子通过调控远端靶基因FAM189A2，参与指导定型内胚层的形成。综上，本研究结果证实转座元件可作为机械力传感器，且转座元件增强子可调控细胞命运决定。实验整体设计：将细胞接种于不同刚度的水凝胶基质上培养，随后收集样本进行RNA测序（RNA-seq）、染色质免疫共沉淀测序（ChIP-seq）及HiCAR检测。