Almassalha Luay M, MacQuarrie Kyle L, Carignano Marcelo, Dunton Cody, Gong Ruyi, Ibarra Joe, Carter Lucas M, Li Wing Shun, Nap Rikkert, Dulai Parambir S, Szleifer Igal, Backman Vadim
Division of Gastroenterology and Hepatology, Northwestern Memorial Hospital, Chicago, IL 60611, USA.
Center for Physical Genomics and Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
bioRxiv. 2025 May 29:2025.05.29.656862. doi: 10.1101/2025.05.29.656862.
Human tissues require a mechanism to generate durable, yet modifiable, transcriptional memories to sustain cell function across a lifetime. Previously, we demonstrated that nanoscale packing domains couple heterochromatin (cores) and euchromatin (outer zone) into unified reaction volumes that can generate transcriptional memory. In prior work, this framework demonstrated that RNA synthesis occurred within the ideal zone (intermediate density) portions of the domain. Naturally, this creates a question of where genes are positioned in relation to the packing domain architecture and which genetic material fills the domain core to sustain transcription. Here we propose that this could be solved by the encoded positioning of introns, intergenic segments, and exons as a projection of the functional packing layers of domains. This suggests that introns and intergenic segments are coupled to adjacent exons to generate coherent packing domain volumes. We illustrate how this organization would reconcile contradictions in epigenetic patterns, non-randomness in oncogenic mutations, and produce durable transcriptional memory. We conclude by showing that this genome geometry might have coincided with the rapid evolution of body-plan complexity, suggesting that chromatin geometry could be fundamental to metazoan evolution.
人体组织需要一种机制来产生持久且可修饰的转录记忆，以在整个生命周期中维持细胞功能。此前，我们证明了纳米级包装结构域将异染色质（核心）和常染色质（外部区域）耦合到统一的反应空间中，从而产生转录记忆。在之前的工作中，该框架表明RNA合成发生在结构域的理想区域（中等密度）部分。自然而然地，这就产生了一个问题：基因相对于包装结构域架构位于何处，以及哪些遗传物质填充结构域核心以维持转录。在这里，我们提出这可以通过内含子、基因间区段和外显子的编码定位来解决，作为结构域功能包装层的一种投射。这表明内含子和基因间区段与相邻的外显子耦合，以产生连贯的包装结构域空间。我们说明了这种组织方式如何协调表观遗传模式中的矛盾、致癌突变的非随机性，并产生持久的转录记忆。我们最后指出，这种基因组几何结构可能与身体结构复杂性的快速进化同时出现，这表明染色质几何结构可能是后生动物进化的基础。
