Laboratoire de Biologie et Modélisation de la Cellule, École Normale Supérieure de Lyon, CNRS, UMR5239, Inserm U1293, Université Claude Bernard Lyon 1, 46 Allée d'Italie, 69007 Lyon, France.
École Normale Supérieure de Lyon, CNRS, Laboratoire de Physique, 46 Allée d'Italie, 69007 Lyon, France.
Nucleic Acids Res. 2022 Sep 9;50(16):9083-9104. doi: 10.1093/nar/gkac702.
In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of 'reader-writer' enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encoded by post-translational modifications of histone tails. Based on experimental knowledge, we introduce a unified modeling framework, the painter model, describing the mechanistic interplay between sequence-specific recruitment of chromatin regulators, chromatin-state-specific reader-writer processes and long-range spreading mechanisms. A systematic analysis of the model building blocks highlights the crucial impact of tridimensional chromatin organization and state-specific recruitment of enzymes on the stability of epigenomic domains and on gene expression. In particular, we show that enhanced 3D compaction of the genome and enzyme limitation facilitate the formation of ultra-stable, confined chromatin domains. The model also captures how chromatin state dynamics impact the intrinsic transcriptional properties of the region, slower kinetics leading to noisier expression. We finally apply our framework to analyze experimental data, from the propagation of γH2AX around DNA breaks in human cells to the maintenance of heterochromatin in fission yeast, illustrating how the painter model can be used to extract quantitative information on epigenomic molecular processes.
在真核生物中，许多稳定且可遗传的表型是由相同的 DNA 序列产生的，这归因于依赖“读取器-写入器”酶的分子协同作用的表观遗传调控机制。在这项工作中，我们专注于组蛋白尾部翻译后修饰所编码的表观基因组记忆背后的基本通用机制。基于实验知识，我们引入了一个统一的建模框架，即画家模型，描述了染色质调节剂的序列特异性募集、染色质状态特异性读取器-写入器过程和长程扩展机制之间的机制相互作用。对模型构建块的系统分析突出了三维染色质组织和酶的状态特异性募集对表观基因组域稳定性和基因表达的关键影响。特别是，我们表明基因组的增强的三维压缩和酶的限制有助于形成超稳定的、受限的染色质域。该模型还捕获了染色质状态动力学如何影响该区域的固有转录特性，较慢的动力学导致更嘈杂的表达。我们最后应用我们的框架来分析实验数据，从人类细胞中 DNA 断裂周围的 γH2AX 的传播到裂殖酵母中异染色质的维持，说明了画家模型如何用于提取关于表观基因组分子过程的定量信息。
