Epigenetic factor competition reshapes the EMT landscape.
Epigenetic factor competition reshapes the EMT landscape.
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DOI：
10.1073/pnas.2210844119
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发表时间：
2022-10-18
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
表观遗传学指的是基因组中结构修饰的作用，这些结构修饰编码了控制基因表达动力学的背景。虽然已经尝试建立这些结构变化的数学模型，但这些变化如何与转录电路耦合仍然不清楚。在这里，我们研究组蛋白修饰的作用，即添加或删除甲基组蛋白H3的尾巴，在相互作用与调控因子之间的上皮和间充质表型的转换。我们的研究结果表明，考虑到脱靶的全球影响，由于不同的DNA片段之间的竞争相同的组蛋白修饰酶的至关重要的。同基因细胞中不同表型的出现和转变可以归因于表观遗传标记、外部信号和基因调控元件的复杂相互作用。这些元件包括染色质重塑剂、组蛋白修饰剂、转录因子和调节RNA。被称为基因调控网络（GRNs）的数学模型是一种越来越重要的工具，可以揭示这种复杂网络的运作。在这样的模型中，表观遗传因素通常被认为作用于直接参与相关基因表达的染色质区域。然而，已经确定的是，这些因素在全球范围内运作，并在全基因组范围内相互竞争靶点。因此，调节因子活性的扰动可以在基因组中重新分布表观遗传标记，并调节竞争调节因子的水平。在本文中，我们提出了一个概念和数学建模框架，结合了本地和全球的竞争效应之间的拮抗表观遗传调节，除了本地转录因子，并显示这种相互作用的反直觉的后果。我们将我们的方法应用于上皮-间质转化（EMT）的最新实验结果。我们表明，它可以解释令人困惑的实验数据，以及提供可验证的预测。
Epigenetics refers to the role of structural modifications in the genome that encode the context governing gene-expression dynamics. Although there have been attempts at creating mathematical models of these structural changes, how these changes couple to the transcriptional circuitry has remained unclear. Here, we study the role of histone modifications—namely, the adding or removing of methyl groups from histone H3 tails—in interacting with regulatory factors governing the transitions between epithelial and mesenchymal phenotypes. Our results show the critical importance of taking into account off-target global effects due to the competition between different DNA segments for the same histone-modifying enzymes. The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene-regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as gene-regulatory networks (GRNs) are an increasingly important tool to unravel the workings of such complex networks. In such models, epigenetic factors are usually proposed to act on the chromatin regions directly involved in the expression of relevant genes. However, it has been well-established that these factors operate globally and compete with each other for targets genome-wide. Therefore, a perturbation of the activity of a regulator can redistribute epigenetic marks across the genome and modulate the levels of competing regulators. In this paper, we propose a conceptual and mathematical modeling framework that incorporates both local and global competition effects between antagonistic epigenetic regulators, in addition to local transcription factors, and show the counterintuitive consequences of such interactions. We apply our approach to recent experimental findings on the epithelial–mesenchymal transition (EMT). We show that it can explain the puzzling experimental data, as well as provide verifiable predictions.
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影响因子：
30.8
作者：
Douillet D;Sze CC;Ryan C;Piunti A;Shah AP;Ugarenko M;Marshall SA;Rendleman EJ;Zha D;Helmin KA;Zhao Z;Cao K;Morgan MA;Singer BD;Bartom ET;Smith ER;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
16
作者：
Chaouch, Amel;Berlandi, Johannes;Chen, Carol C. L.;Frey, Felice;Badini, Shireen;Harutyunyan, Ashot S.;Chen, Xiao;Krug, Brian;Hebert, Steven;Jeibmann, Astrid;Lu, Chao;Kleinman, Claudia L.;Hasselblatt, Martin;Lasko, Paul;Shirinian, Margret;Jabado, Nada
通讯作者：
Jabado, Nada
DOI：
10.1073/pnas.1511377112
发表时间：
2015-11-17
影响因子：
11.1
作者：
Basenko, Evelina Y.;Sasaki, Takahiko;Lewis, Zachary A.
通讯作者：
Lewis, Zachary A.
影响因子：
4.3
作者：
Alarcón T;Sardanyés J;Guillamon A;Menendez JA
通讯作者：
Menendez JA
影响因子：
8
作者：
Gala K;Li Q;Sinha A;Razavi P;Dorso M;Sanchez-Vega F;Chung YR;Hendrickson R;Hsieh JJ;Berger M;Schultz N;Pastore A;Abdel-Wahab O;Chandarlapaty S
通讯作者：
Chandarlapaty S