Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets-Recent Insights at Molecular and Cellular Level.
Exploration of the Noncoding Genome for Human-Specific Therapeutic Targets-Recent Insights at Molecular and Cellular Level.
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探索人类特异性治疗靶点的非编码基因组-在分子和细胞水平上的最新见解。
作者：
虽然众所周知，98-99%的人类基因组不编码蛋白质，但仍然具有转录活性，并产生广泛的非编码RNA[ncRNAs]，具有复杂的调节和结构功能，但到目前为止，特定的功能只被分配给所有已知转录本中的一小部分。另一方面，在从简单生物到人类的进化过程中，惊人地观察到ncRNAs比例的压倒性增长，而蛋白质编码基因的数量仅略有增加，这有力地表明了非编码基因组对人类健康和疾病发病机制的关键但基本上尚未被探索的作用。在过去的几十年里，对非编码基因组这一广阔领域的研究使人们对人类基因组的多层次复杂性有了深刻的认识。在这里，我们解决许多巨大的剩余知识差距中的几个，并考虑一些新出现的研究问题和概念。我们试图提供通过分子和细胞生物学方法以及通过应用系统生物学方法获得的最新见解的最新评估。具体地说，我们讨论了关于两个当前感兴趣的话题的当前数据：(1)在广泛的细胞类型(神经、免疫、心血管)中进化具有关键调节功能的新近的ncRNAs通过什么机制可以构成人类疾病的新的治疗靶点？(2)由于非编码基因组进化与大脑进化有因果关系，并且考虑到大脑和免疫系统之间的深刻相互作用，人类特定大脑表达的ncRNAs能否在人类疾病中发挥直接或间接(免疫介导的)作用？随着最近在核酸治疗的交付、有效性和安全性方面取得的显著进展，正在进行的针对人类特定治疗靶点的非编码基因组的大规模探索令人鼓舞地继续这些研究领域提出的新治疗途径的开发和临床评估。
While it is well known that 98–99% of the human genome does not encode proteins, but are nevertheless transcriptionally active and give rise to a broad spectrum of noncoding RNAs [ncRNAs] with complex regulatory and structural functions, specific functions have so far been assigned to only a tiny fraction of all known transcripts. On the other hand, the striking observation of an overwhelmingly growing fraction of ncRNAs, in contrast to an only modest increase in the number of protein-coding genes, during evolution from simple organisms to humans, strongly suggests critical but so far essentially unexplored roles of the noncoding genome for human health and disease pathogenesis. Research into the vast realm of the noncoding genome during the past decades thus lead to a profoundly enhanced appreciation of the multi-level complexity of the human genome. Here, we address a few of the many huge remaining knowledge gaps and consider some newly emerging questions and concepts of research. We attempt to provide an up-to-date assessment of recent insights obtained by molecular and cell biological methods, and by the application of systems biology approaches. Specifically, we discuss current data regarding two topics of high current interest: (1) By which mechanisms could evolutionary recent ncRNAs with critical regulatory functions in a broad spectrum of cell types (neural, immune, cardiovascular) constitute novel therapeutic targets in human diseases? (2) Since noncoding genome evolution is causally linked to brain evolution, and given the profound interactions between brain and immune system, could human-specific brain-expressed ncRNAs play a direct or indirect (immune-mediated) role in human diseases? Synergistic with remarkable recent progress regarding delivery, efficacy, and safety of nucleic acid-based therapies, the ongoing large-scale exploration of the noncoding genome for human-specific therapeutic targets is encouraging to proceed with the development and clinical evaluation of novel therapeutic pathways suggested by these research fields.
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DOI：
10.2147/tacg.s383453
发表时间：
2023
期刊：
The application of clinical genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.5
作者：
Baird DA;Liu JZ;Zheng J;Sieberts SK;Perumal T;Elsworth B;Richardson TG;Chen CY;Carrasquillo MM;Allen M;Reddy JS;De Jager PL;Ertekin-Taner N;Mangravite LM;Logsdon B;Estrada K;Haycock PC;Hemani G;Runz H;Smith GD;Gaunt TR;AMP-AD eQTL working group
通讯作者：
AMP-AD eQTL working group
影响因子：
11
作者：
Cao J;Huang M;Guo L;Zhu L;Hou J;Zhang L;Pero A;Ng S;El Gaamouch F;Elder G;Sano M;Goate A;Tcw J;Haroutunian V;Zhang B;Cai D
通讯作者：
Cai D
影响因子：
3.1
作者：
Alnaqbi, Nada;Mohammad, Mohammad G.;Hamoudi, Rifat;Mabondzo, Aloise;Harati, Rania
通讯作者：
Harati, Rania
DOI：
10.3390/v15051086
发表时间：
2023-04-28
期刊：
Viruses
影响因子：
--
作者：
Bates EA;Lovatt C;Plein AR;Davies JA;Siebzehnrubl FA;Parker AL
通讯作者：
Parker AL