Department of Chemistry, New York University, New York, NY 10003.
Department of Chemistry, New York University, New York, NY 10003;
Proc Natl Acad Sci U S A. 2019 Mar 12;116(11):4955-4962. doi: 10.1073/pnas.1816424116. Epub 2019 Feb 4.
Gene expression is orchestrated at the structural level by nucleosome positioning, histone tail acetylation, and linker histone (LH) binding. Here, we integrate available data on nucleosome positioning, nucleosome-free regions (NFRs), acetylation islands, and LH binding sites to "fold" in silico the 55-kb HOXC gene cluster and investigate the role of each feature on the gene's folding. The gene cluster spontaneously forms a dynamic connection hub, characterized by hierarchical loops which accommodate multiple contacts simultaneously and decrease the average distance between promoters by ∼100 nm. Contact probability matrices exhibit "stripes" near promoter regions, a feature associated with transcriptional regulation. Interestingly, while LH proteins alone decrease long-range contacts and acetylation alone increases transient contacts, combined LH and acetylation produce long-range contacts. Thus, our work emphasizes how chromatin architecture is coordinated strongly by epigenetic factors and opens the way for nucleosome resolution models incorporating epigenetic modifications to understand and predict gene activity.
基因表达在结构水平上是由核小体定位、组蛋白尾部乙酰化和连接组蛋白（LH）结合来协调的。在这里，我们整合了核小体定位、无核小体区域（NFR）、乙酰化岛和 LH 结合位点的现有数据，以“折叠”HOXC 基因簇的 55kb 基因簇，并研究每个特征对基因折叠的作用。该基因簇自发形成一个动态连接枢纽，其特征是层次结构环，可同时容纳多个接触点，并将启动子之间的平均距离减小约 100nm。接触概率矩阵在启动子区域附近显示“条纹”，这是与转录调控相关的特征。有趣的是，虽然 LH 蛋白本身可以减少长程接触，而乙酰化本身可以增加瞬时接触，但 LH 和乙酰化的组合可以产生长程接触。因此，我们的工作强调了染色质结构如何受到表观遗传因素的强烈协调，并为整合表观遗传修饰的核小体分辨率模型打开了道路，以理解和预测基因活性。
