Department of Chemistry, Stanford University, Stanford, CA 94305.
Department of Physics, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20423-20429. doi: 10.1073/pnas.1920499117. Epub 2020 Aug 10.
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.
我们开发了一个预测性的理论模型，用于研究控制表观遗传修饰的遗传和维持的物理机制。该模型专注于一种特定的修饰，即组蛋白 H3 赖氨酸-9 的甲基化（H3K9），它是影响染色质组织和基因表达的最具代表性和关键的表观遗传标记之一。我们的模型将分离和压缩对染色体组织的影响与影响染色质紧缩的蛋白质（异染色质蛋白 1）与影响甲基化扩散的甲基转移酶之间的相互作用的影响结合起来。我们的染色质模型表明，在表观遗传序列中的 H3K9 甲基化块决定了在染色质的任何特定位置的压缩状态。使用我们的染色质紧缩预测模型，我们开发了一个甲基化模型来解决 DNA 复制后甲基化序列的重新建立问题。我们的模型能够可靠地维持甲基化在几代中的存在，从而建立了表观遗传密码的稳健性。
