School of Physical Science and Technology, Inner Mongolia University, Hohhot 010021, China.
The State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China.
Int J Mol Sci. 2024 Oct 15;25(20):11048. doi: 10.3390/ijms252011048.
Aberrant DNA methylation plays a crucial role in breast cancer progression by regulating gene expression. However, the regulatory pattern of DNA methylation in long noncoding RNAs (lncRNAs) for breast cancer remains unclear. In this study, we integrated gene expression, DNA methylation, and clinical data from breast cancer patients included in The Cancer Genome Atlas (TCGA) database. We examined DNA methylation distribution across various lncRNA categories, revealing distinct methylation characteristics. Through genome-wide correlation analysis, we identified the CpG sites located in lncRNAs and the distally associated CpG sites of lncRNAs. Functional genome enrichment analysis, conducted through the integration of ENCODE ChIP-seq data, revealed that differentially methylated CpG sites (DMCs) in lncRNAs were mostly located in promoter regions, while distally associated DMCs primarily acted on enhancer regions. By integrating Hi-C data, we found that DMCs in enhancer and promoter regions were closely associated with the changes in three-dimensional chromatin structures by affecting the formation of enhancer-promoter loops. Furthermore, through Cox regression analysis and three machine learning models, we identified 11 key methylation-driven lncRNAs (DIO3OS, ELOVL2-AS1, MIAT, LINC00536, C9orf163, AC105398.1, LINC02178, MILIP, HID1-AS1, KCNH1-IT1, and TMEM220-AS1) that were associated with the survival of breast cancer patients and constructed a prognostic risk scoring model, which demonstrated strong prognostic performance. These findings enhance our understanding of DNA methylation's role in lncRNA regulation in breast cancer and provide potential biomarkers for diagnosis.
异常的 DNA 甲基化通过调控基因表达在乳腺癌的进展中起着至关重要的作用。然而，乳腺癌中长链非编码 RNA（lncRNA）的 DNA 甲基化调控模式尚不清楚。在这项研究中，我们整合了来自癌症基因组图谱（TCGA）数据库中包含的乳腺癌患者的基因表达、DNA 甲基化和临床数据。我们检查了各种 lncRNA 类别中的 DNA 甲基化分布，揭示了不同的甲基化特征。通过全基因组相关性分析，我们确定了位于 lncRNA 中的 CpG 位点和 lncRNA 的远端相关 CpG 位点。通过整合 ENCODE ChIP-seq 数据进行的功能基因组富集分析表明，lncRNA 中差异甲基化的 CpG 位点（DMCs）主要位于启动子区域，而远端相关的 DMCs 主要作用于增强子区域。通过整合 Hi-C 数据，我们发现增强子和启动子区域中的 DMCs 通过影响增强子-启动子环的形成，与三维染色质结构变化密切相关。此外，通过 Cox 回归分析和三种机器学习模型，我们确定了 11 个关键的甲基化驱动的 lncRNA（DIO3OS、ELOVL2-AS1、MIAT、LINC00536、C9orf163、AC105398.1、LINC02178、MILIP、HID1-AS1、KCNH1-IT1 和 TMEM220-AS1），它们与乳腺癌患者的生存相关，并构建了一个预后风险评分模型，该模型表现出了强大的预后性能。这些发现增强了我们对 DNA 甲基化在乳腺癌中 lncRNA 调控中的作用的理解，并为诊断提供了潜在的生物标志物。
