Institute of Zoology (Biology 2), Division of Neuroepigenetics, RWTH Aachen University, Worringerweg 3, 52074, Aachen, Germany.
Research Training Group 2416 Multi Senses - Multi Scales, RWTH Aachen University, 52074, Aachen, Germany.
Epigenetics Chromatin. 2023 Oct 26;16(1):42. doi: 10.1186/s13072-023-00516-4.
Cell-cell communication is mediated by membrane receptors and their ligands, such as the Eph/ephrin system, orchestrating cell migration during development and in diverse cancer types. Epigenetic mechanisms are key for integrating external "signals", e.g., from neighboring cells, into the transcriptome in health and disease. Previously, we reported ephrinA5 to trigger transcriptional changes of lncRNAs and protein-coding genes in cerebellar granule cells, a cell model for medulloblastoma. LncRNAs represent important adaptors for epigenetic writers through which they regulate gene expression. Here, we investigate a lncRNA-mediated targeting of DNMT1 to specific gene loci by the combined power of in silico modeling of RNA/DNA interactions and wet lab approaches, in the context of the clinically relevant use case of ephrinA5-dependent regulation of cellular motility of cerebellar granule cells. We provide evidence that Snhg15, a cancer-related lncRNA, recruits DNMT1 to the Ncam1 promoter through RNA/DNA triplex structure formation and the interaction with DNMT1. This mediates DNA methylation-dependent silencing of Ncam1, being abolished by ephrinA5 stimulation-triggered reduction of Snhg15 expression. Hence, we here propose a triple helix recognition mechanism, underlying cell motility regulation via lncRNA-targeted DNA methylation in a clinically relevant context.
细胞间通讯是通过膜受体及其配体介导的，例如 Eph/ephrin 系统，在发育过程中和多种癌症类型中协调细胞迁移。表观遗传机制是将外部“信号”（例如来自相邻细胞的信号）整合到健康和疾病中的转录组中的关键。以前，我们报道 EphrinA5 可引发小脑颗粒细胞中转录本的长非编码 RNA 和蛋白质编码基因的变化，小脑颗粒细胞是成神经管细胞瘤的细胞模型。长非编码 RNA 是表观遗传作家的重要衔接子，通过它们来调节基因表达。在这里，我们通过 RNA/DNA 相互作用的计算机建模和湿实验室方法的结合，研究了 lncRNA 介导的 DNMT1 对特定基因座的靶向，这是 EphrinA5 依赖性调节小脑颗粒细胞细胞运动的临床相关用例的背景。我们提供的证据表明，癌症相关的长非编码 RNA Snhg15 通过 RNA/DNA 三螺旋结构形成和与 DNMT1 的相互作用，将 DNMT1 募集到 Ncam1 启动子。这介导了 Ncam1 的 DNA 甲基化依赖性沉默，EphrinA5 刺激引发的 Snhg15 表达减少会使其失活。因此，我们在这里提出了一种三螺旋识别机制，它通过 lncRNA 靶向的 DNA 甲基化来调节细胞运动，这在临床相关的背景下具有重要意义。
