Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA.
BMC Genomics. 2021 Oct 21;22(Suppl 3):754. doi: 10.1186/s12864-021-08052-9.
Various epigenetic factors are responsible for the non-genetic regulation on gene expression. The epigenetically dysregulated oncogenes or tumor suppressors by miRNA and/or DNA methylation are often observed in cancer cells. Each of these epigenetic regulators has been studied well in cancer progressions; however, their mutual regulatory relationship in cancer still remains unclear. In this study, we propose an integrative framework to systematically investigate epigenetic interactions between miRNA and methylation at the alternatively spliced mRNA level in bladder cancer. Each of these epigenetic regulators has been studied well in cancer progressions; however, their mutual regulatory relationship in cancer still remains unclear.
The integrative analyses yielded 136 significant combinations (methylation, miRNA and isoform). Further, overall survival analysis on the 136 combinations based on methylation and miRNA, high and low expression groups resulted in 13 combinations associated with survival. Additionally, different interaction patterns were examined.
Our study provides a higher resolution of molecular insight into the crosstalk between two epigenetic factors, DNA methylation and miRNA. Given the importance of epigenetic interactions and alternative splicing in cancer, it is timely to identify and understand the underlying mechanisms based on epigenetic markers and their interactions in cancer, leading to alternative splicing with primary functional impact.
各种表观遗传因素负责基因表达的非遗传调控。miRNA 和/或 DNA 甲基化导致的表观遗传失调的癌基因或肿瘤抑制因子在癌细胞中经常观察到。这些表观遗传调节剂中的每一种在癌症进展中都得到了很好的研究；然而，它们在癌症中的相互调节关系仍然不清楚。在这项研究中，我们提出了一个综合框架，系统地研究膀胱癌中 miRNA 和甲基化在可变剪接 mRNA 水平上的表观遗传相互作用。这些表观遗传调节剂中的每一种在癌症进展中都得到了很好的研究；然而，它们在癌症中的相互调节关系仍然不清楚。
综合分析产生了 136 个显著组合（甲基化、miRNA 和异构体）。进一步基于甲基化和 miRNA 的高、低表达组对 136 个组合进行总生存分析，得到了 13 个与生存相关的组合。此外，还检查了不同的相互作用模式。
我们的研究提供了对两个表观遗传因素，DNA 甲基化和 miRNA 之间相互作用的更高分辨率的分子见解。鉴于表观遗传相互作用和可变剪接在癌症中的重要性，及时识别和理解基于表观遗传标记及其在癌症中的相互作用的潜在机制，导致具有主要功能影响的可变剪接是及时的。
