Physical modeling of the heritability and maintenance of epigenetic modifications
Physical modeling of the heritability and maintenance of epigenetic modifications
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DOI：
10.1073/pnas.1920499117
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发表时间：
2020-08
期刊：
影响因子：
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通讯作者：
Sarah H. Sandholtz;Quinn MacPherson;A. Spakowitz
中科院分区：
文献类型：
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作者：
Sarah H. Sandholtz;Quinn MacPherson;A. Spakowitz
表观遗传调控是多细胞生物体将遗传相同的细胞分化为各种细胞类型的基础，表观遗传修饰中的畸变导致一系列疾病。表观遗传修饰的遗传性和维持性背后的具体生物学机制目前还不清楚。我们开发了一个预测性的理论模型之间的相互作用的蛋白质控制染色体压实和那些赋予染色体DNA内的组蛋白的翻译后修饰。我们的模型是建立在这些个体生物学贡献的实验观察行为的基础上的，从而产生了一个预测框架，该框架捕获了表观遗传遗传性的强大机制。我们开发了一个预测性的理论模型的物理机制，管理的遗传性和维持表观遗传修饰。该模型侧重于一种特殊的修饰，即组蛋白H3（H3 K9）赖氨酸-9的甲基化，这是影响染色质组织和基因表达的最具代表性和关键性的表观遗传标记之一。我们的模型结合了染色体组织的分离和压实的效果与蛋白质之间的相互作用，紧凑的染色质（异染色质蛋白1）和甲基转移酶，影响甲基扩散的效果。我们的染色质模型表明，在表观遗传序列中的H3 K9甲基化的块决定在染色质中的任何特定位置的压实状态。使用我们的预测模型染色质压实，我们开发了一个甲基化模型，以解决DNA复制后甲基化序列的重建。我们的模型可靠地保持了几代人的甲基化，从而建立了表观遗传密码的鲁棒性。
Significance Epigenetic regulation serves as the basis on which multicellular organisms differentiate genetically identical cells into various cell types, and aberrations in epigenetic modifications lead to a range of diseases. The specific biological mechanisms behind the heritability and maintenance of epigenetic modifications are currently not well understood. We develop a predictive theoretical model of the interplay between the proteins that control chromosomal compaction and those that confer posttranslational modifications to histone proteins within chromosomal DNA. Our model is built on the experimentally observed behavior for these individual biological contributions, resulting in a predictive framework that captures a robust mechanism for epigenetic heritability. We develop a predictive theoretical model of the physical mechanisms that govern the heritability and maintenance of epigenetic modifications. This model focuses on a particular modification, methylation of lysine-9 of histone H3 (H3K9), which is one of the most representative and critical epigenetic marks that affects chromatin organization and gene expression. Our model combines the effect of segregation and compaction on chromosomal organization with the effect of the interaction between proteins that compact the chromatin (heterochromatin protein 1) and the methyltransferases that affect methyl spreading. Our chromatin model demonstrates that a block of H3K9 methylations in the epigenetic sequence determines the compaction state at any particular location in the chromatin. Using our predictive model for chromatin compaction, we develop a methylation model to address the reestablishment of the methylation sequence following DNA replication. Our model reliably maintains methylation over generations, thereby establishing the robustness of the epigenetic code.