Cooperative RNA degradation stabilizes intermediate epithelial-mesenchymal states and supports a phenotypic continuum.
Cooperative RNA degradation stabilizes intermediate epithelial-mesenchymal states and supports a phenotypic continuum.
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DOI：
10.1016/j.isci.2022.105224
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发表时间：
2022-10-21
期刊：
影响因子：
5.8
通讯作者：
Hong, Tian
中科院分区：
文献类型：
--
作者：
Nordick, Benjamin;Park, Mary Chae-Yeon;Quaranta, Vito;Hong, Tian
在生理和病理条件下观察到多种反映混合上皮和间充质表型的中间上皮-间充质转变(EMT)状态。以前解释多个EMT状态的理论模型依赖于涉及转录反馈的调控环，这些调控环产生三到四个吸引子。这与观测到的连续体样EMT谱不相容。在这里，我们使用基于质量作用的模型来描述转录后调控，发现通过多个microRNA结合位点的协同RNA降解可以在没有转录反馈的情况下产生四个吸引子系统。此外，新发现的中间体使能回路在EMT调控网络中很常见，它们可以与转录反馈协同作用来支持表型连续体。最后，我们的模型预测了miR-101在多态EMT中的作用，并从单细胞RNA测序数据中确定了支持这一预测的证据。我们的工作揭示了协同RNA降解和microRNAs在EMT中先前未知的作用，提供了一个框架，可以弥合机制模型和单细胞实验之间的差距。单单协同降解就可以产生三种共存的细胞状态转录和RNA衰变电路协同控制高阶多稳定性RNA衰变电路支持上皮-间充质可塑性模型和单细胞数据显示microRNA-101‘S在控制多态EMT中的作用基因调控的分子机制；数学生物科学
Multiple intermediate epithelial-mesenchymal transition (EMT) states reflecting hybrid epithelial and mesenchymal phenotypes were observed in physiological and pathological conditions. Previous theoretical models explaining multiple EMT states rely on regulatory loops involving transcriptional feedback, which produce three or four attractors. This is incompatible with the observed continuum-like EMT spectrum. Here, we used mass-action-based models to describe post-transcriptional regulations, finding that cooperative RNA degradation via multiple microRNA binding sites can generate four-attractor systems without transcriptional feedback. Furthermore, the newly identified intermediates-enabling circuits are common in the EMT regulatory network, and they can synergize with transcriptional feedback to support phenotypic continuum. Finally, our model predicted a role of miR-101 in multistate EMT, and we identified evidence from single-cell RNA-sequencing data that support the prediction. Our work reveals a previously unknown role of cooperative RNA degradation and microRNAs in EMT, providing a framework that can bridge the gap between mechanistic models and single-cell experiments. Cooperative RNA degradation alone can generate three co-existing cell states Transcription and RNA-decay circuits synergize to govern high-order multistability RNA-decay circuits support continuum of epithelial-mesenchymal plasticity Models and single-cell data show microRNA-101’s role in controlling multistate EMT Molecular mechanism of gene regulation; Mathematical biosciences
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EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
DOI：
10.1016/j.biosystems.2018.07.006
发表时间：
2018-09
期刊：
Bio Systems
影响因子：
--
作者：
Choi K;Medley JK;König M;Stocking K;Smith L;Gu S;Sauro HM
通讯作者：
Sauro HM
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
影响因子：
11.2
作者：
Bracken, Cameron P.;Gregory, Philip A.;Goodall, Gregory J.
通讯作者：
Goodall, Gregory J.
影响因子：
4.3
作者：
Huang B;Lu M;Jia D;Ben-Jacob E;Levine H;Onuchic JN
通讯作者：
Onuchic JN