Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Department of Biomedical Engineering, Georgia Institute of Technology, UAW 3108, 313 Ferst Drive NW, Atlanta, GA, 30332, USA.
BMC Genomics. 2023 Jul 13;24(1):395. doi: 10.1186/s12864-023-09498-9.
Many long non-coding RNAs, known to be involved in transcriptional regulation, are enriched in the nucleus and interact with chromatin. However, their mechanisms of chromatin interaction and the served cellular functions are poorly understood. We sought to characterize the mechanisms of lncRNA nuclear retention by systematically mapping the sequence and chromatin features that distinguish lncRNA-interacting genomic segments.
We found DNA 5-mer frequencies to be predictive of chromatin interactions for all lncRNAs, suggesting sequence-specificity as a global theme in the interactome. Sequence features representing protein-DNA and protein-RNA binding motifs revealed potential mechanisms for specific lncRNAs. Complementary to these global themes, transcription-related features and DNA-RNA triplex formation potential were noted to be highly predictive for two mutually exclusive sets of lncRNAs. DNA methylation was also noted to be a significant predictor, but only when combined with other epigenomic features.
Taken together, our statistical findings suggest that a group of lncRNAs interacts with transcriptionally inactive chromatin through triplex formation, whereas another group interacts with transcriptionally active regions and is involved in DNA Damage Response (DDR) through formation of R-loops. Curiously, we observed a strong pattern of enrichment of 5-mers in four potentially interacting entities: lncRNA-bound DNA tiles, lncRNAs, miRNA seed sequences, and repeat elements. This finding points to a broad sequence-based network of interactions that may underlie regulation of fundamental cellular functions. Overall, this study reveals diverse sequence and chromatin features related to lncRNA-chromatin interactions, suggesting potential mechanisms of nuclear retention and regulatory function.
许多长非编码 RNA 参与转录调控，它们在核内富集并与染色质相互作用。然而，它们与染色质相互作用的机制和所服务的细胞功能仍知之甚少。我们试图通过系统地绘制区分 lncRNA 相互作用基因组片段的序列和染色质特征，来描述 lncRNA 核保留的机制。
我们发现所有 lncRNA 的 DNA 5- mers 频率可预测染色质相互作用，这表明序列特异性是互作组中的一个全局主题。代表蛋白-DNA 和蛋白-RNA 结合基序的序列特征揭示了特定 lncRNA 的潜在机制。与这些全局主题互补的是，转录相关特征和 DNA-RNA 三链体形成潜力高度预测了两组相互排斥的 lncRNA。值得注意的是，DNA 甲基化也是一个重要的预测因素，但仅在与其他表观遗传特征结合时才如此。
总的来说，我们的统计发现表明，一组 lncRNA 通过三链体形成与转录不活跃的染色质相互作用，而另一组与转录活跃区域相互作用，并通过形成 R 环参与 DNA 损伤反应 (DDR)。奇怪的是，我们观察到在四个潜在相互作用的实体中，5- mers 的富集模式很强：lncRNA 结合的 DNA 平铺、lncRNA、miRNA 种子序列和重复元件。这一发现指向了一个广泛的基于序列的相互作用网络，可能是基本细胞功能调控的基础。总体而言，这项研究揭示了与 lncRNA-染色质相互作用相关的多种序列和染色质特征，表明了核保留和调节功能的潜在机制。
