Centre for Biosystems & Genomic Network Medicine, Ioannina University, Ioannina, Greece.
Wiley Interdiscip Rev Syst Biol Med. 2014 Mar-Apr;6(2):201-8. doi: 10.1002/wsbm.1254. Epub 2013 Dec 6.
The post-ENCODE era shapes now a new biomedical research direction for understanding transcriptional and signaling networks driving gene expression and core cellular processes such as cell fate, survival, and apoptosis. Over the past half century, the Francis Crick 'central dogma' of single n gene/protein-phenotype (trait/disease) has defined biology, human physiology, disease, diagnostics, and drugs discovery. However, the ENCODE project and several other genomic studies using high-throughput sequencing technologies, computational strategies, and imaging techniques to visualize regulatory networks, provide evidence that transcriptional process and gene expression are regulated by highly complex dynamic molecular and signaling networks. This Focus article describes the linear experimentation-based limitations of diagnostics and therapeutics to cure advanced cancer and the need to move on from reductionist to network-based approaches. With evident a wide genomic heterogeneity, the power and challenges of next-generation sequencing (NGS) technologies to identify a patient's personal mutational landscape for tailoring the best target drugs in the individual patient are discussed. However, the available drugs are not capable of targeting aberrant signaling networks and research on functional transcriptional heterogeneity and functional genome organization is poorly understood. Therefore, the future clinical genome network medicine aiming at overcoming multiple problems in the new fields of regulatory DNA mapping, noncoding RNA, enhancer RNAs, and dynamic complexity of transcriptional circuitry are also discussed expecting in new innovation technology and strong appreciation of clinical data and evidence-based medicine. The problematic and potential solutions in the discovery of next-generation, molecular, and signaling circuitry-based biomarkers and drugs are explored.
在后 ENCODE 时代，人们形成了一个新的生物医学研究方向，旨在理解转录和信号网络，这些网络驱动基因表达和核心细胞过程，如细胞命运、存活和凋亡。在过去的半个世纪里，弗朗西斯·克里克（Francis Crick）的单一基因/蛋白质-表型（特征/疾病）的“中心法则”定义了生物学、人类生理学、疾病、诊断和药物发现。然而，ENCODE 项目和其他几项使用高通量测序技术、计算策略和成像技术来可视化调控网络的基因组研究表明，转录过程和基因表达受到高度复杂的动态分子和信号网络的调控。本文重点介绍了基于线性实验的诊断和治疗方法在治愈晚期癌症方面的局限性，以及从还原论到基于网络的方法转变的必要性。鉴于明显的广泛基因组异质性，讨论了下一代测序（NGS）技术在识别患者个体突变景观以针对个体患者定制最佳靶向药物方面的优势和挑战。然而，现有的药物无法靶向异常信号网络，对功能转录异质性和功能基因组组织的研究也知之甚少。因此，未来的临床基因组网络医学旨在克服调控 DNA 图谱、非编码 RNA、增强子 RNA 以及转录电路动态复杂性等新领域中的多个问题，同时也期待着新技术的创新和对临床数据和循证医学的强烈关注。本文还探讨了在下一代分子和信号电路生物标志物和药物发现中存在的问题和潜在解决方案。
