Nersisyan Lilit, Simonyan Arman, Binder Hans, Arakelyan Arsen
Bioinformatics Group, Institute of Molecular Biology, National Academy of Sciences, Yerevan, Armenia.
Pathverse, Yerevan, Armenia.
Front Genet. 2021 Apr 7;12:662464. doi: 10.3389/fgene.2021.662464. eCollection 2021.
Telomere maintenance is one of the mechanisms ensuring indefinite divisions of cancer and stem cells. Good understanding of telomere maintenance mechanisms (TMM) is important for studying cancers and designing therapies. However, molecular factors triggering selective activation of either the telomerase dependent (TEL) or the alternative lengthening of telomeres (ALT) pathway are poorly understood. In addition, more accurate and easy-to-use methodologies are required for TMM phenotyping. In this study, we have performed literature based reconstruction of signaling pathways for the ALT and TEL TMMs. Gene expression data were used for computational assessment of TMM pathway activities and compared with experimental assays for TEL and ALT. Explicit consideration of pathway topology makes bioinformatics analysis more informative compared to computational methods based on simple summary measures of gene expression. Application to healthy human tissues showed high ALT and TEL pathway activities in testis, and identified genes and pathways that may trigger TMM activation. Our approach offers a novel option for systematic investigation of TMM activation patterns across cancers and healthy tissues for dissecting pathway-based molecular markers with diagnostic impact.
端粒维持是确保癌细胞和干细胞无限增殖的机制之一。深入了解端粒维持机制（TMM）对于癌症研究和治疗设计至关重要。然而，引发端粒酶依赖性（TEL）或端粒替代延长（ALT）途径选择性激活的分子因素仍知之甚少。此外，TMM表型分析需要更准确、易用的方法。在本研究中，我们基于文献对ALT和TEL TMM的信号通路进行了重建。利用基因表达数据对TMM通路活性进行计算评估，并与TEL和ALT的实验检测结果进行比较。与基于基因表达简单汇总指标的计算方法相比，明确考虑通路拓扑结构使生物信息学分析更具信息量。应用于健康人体组织时，发现睾丸中ALT和TEL通路活性较高，并鉴定出可能触发TMM激活的基因和通路。我们的方法为系统研究癌症和健康组织中的TMM激活模式提供了一种新选择，以剖析具有诊断意义的基于通路的分子标记。
