Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.
PLoS Comput Biol. 2023 Feb 21;19(2):e1010889. doi: 10.1371/journal.pcbi.1010889. eCollection 2023 Feb.
Epigenetic regulatory mechanisms allow multicellular organisms to develop distinct specialized cell identities despite having the same total genome. Cell-fate choices are based on gene expression programs and environmental cues that cells experience during embryonic development, and are usually maintained throughout the life of the organism despite new environmental cues. The evolutionarily conserved Polycomb group (PcG) proteins form Polycomb Repressive Complexes that help orchestrate these developmental choices. Post-development, these complexes actively maintain the resulting cell fate, even in the face of environmental perturbations. Given the crucial role of these polycomb mechanisms in providing phenotypic fidelity (i.e. maintenance of cell fate), we hypothesize that their dysregulation after development will lead to decreased phenotypic fidelity allowing dysregulated cells to sustainably switch their phenotype in response to environmental changes. We call this abnormal phenotypic switching phenotypic pliancy. We introduce a general computational evolutionary model that allows us to test our systems-level phenotypic pliancy hypothesis in-silico and in a context-independent manner. We find that 1) phenotypic fidelity is an emergent systems-level property of PcG-like mechanism evolution, and 2) phenotypic pliancy is an emergent systems-level property resulting from this mechanism's dysregulation. Since there is evidence that metastatic cells behave in a phenotypically pliant manner, we hypothesize that progression to metastasis is driven by the emergence of phenotypic pliancy in cancer cells as a result of PcG mechanism dysregulation. We corroborate our hypothesis using single-cell RNA-sequencing data from metastatic cancers. We find that metastatic cancer cells are phenotypically pliant in the same manner as predicted by our model.
表观遗传调控机制允许多细胞生物在具有相同总基因组的情况下发展出独特的特化细胞身份。细胞命运的选择基于基因表达程序和细胞在胚胎发育过程中经历的环境线索，并且通常在生物体的整个生命周期中保持不变，尽管会有新的环境线索。进化上保守的 Polycomb 组（PcG）蛋白形成 Polycomb 抑制复合物，有助于协调这些发育选择。在发育后，这些复合物积极维持由此产生的细胞命运，即使面对环境干扰也是如此。鉴于这些多梳机制在提供表型保真度（即维持细胞命运）方面的关键作用，我们假设它们在发育后的失调会导致表型保真度降低，从而允许失调的细胞能够可持续地根据环境变化改变其表型。我们将这种异常表型转换称为表型柔韧性。我们引入了一个通用的计算进化模型，使我们能够以独立于上下文的方式在计算机上测试我们的系统级表型柔韧性假设。我们发现：1）表型保真度是 PcG 样机制进化的系统级涌现特性，2）表型柔韧性是该机制失调的系统级涌现特性。由于有证据表明转移性细胞表现出表型柔韧性，我们假设转移性是由于 PcG 机制失调导致癌细胞出现表型柔韧性而发生的。我们使用来自转移性癌症的单细胞 RNA 测序数据来验证我们的假设。我们发现转移性癌细胞的表型柔韧性与我们模型预测的方式相同。
