Weinberg Marc S, Morris Kevin V
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, WITS 2050, South Africa HIV Pathogenesis Research Unit, Department of Molecular Medicine and Haematology, School of Pathology, University of the Witwatersrand, WITS 2050, South Africa.
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA Center for Gene Therapy, City of Hope - BeckmanResearch Institute; Duarte, CA 91010, USA School of Biotechnology and Biomedical Sciences, University of New South Wales, Kensington, NSW, 2033 Australia
Nucleic Acids Res. 2016 Aug 19;44(14):6505-17. doi: 10.1093/nar/gkw139. Epub 2016 Apr 7.
It has been over a decade since the first observation that small non-coding RNAs can functionally modulate epigenetic states in human cells to achieve functional transcriptional gene silencing (TGS). TGS is mechanistically distinct from the RNA interference (RNAi) gene-silencing pathway. TGS can result in long-term stable epigenetic modifications to gene expression that can be passed on to daughter cells during cell division, whereas RNAi does not. Early studies of TGS have been largely overlooked, overshadowed by subsequent discoveries of small RNA-directed post-TGS and RNAi. A reappraisal of early work has been brought about by recent findings in human cells where endogenous long non-coding RNAs function to regulate the epigenome. There are distinct and common overlaps between the proteins involved in small and long non-coding RNA transcriptional regulatory mechanisms, suggesting that the early studies using small non-coding RNAs to modulate transcription were making use of a previously unrecognized endogenous mechanism of RNA-directed gene regulation. Here we review how non-coding RNA plays a role in regulation of transcription and epigenetic gene silencing in human cells by revisiting these earlier studies and the mechanistic insights gained to date. We also provide a list of mammalian genes that have been shown to be transcriptionally regulated by non-coding RNAs. Lastly, we explore how TGS may serve as the basis for development of future therapeutic agents.
自首次观察到小非编码RNA可在人类细胞中功能性调节表观遗传状态以实现功能性转录基因沉默（TGS）以来，已经过去了十多年。TGS在机制上与RNA干扰（RNAi）基因沉默途径不同。TGS可导致对基因表达的长期稳定表观遗传修饰，这种修饰在细胞分裂过程中可传递给子细胞，而RNAi则不会。TGS的早期研究在很大程度上被忽视了，随后小RNA介导的TGS后调控和RNAi的发现使其黯然失色。最近在人类细胞中的发现引发了对早期工作的重新评估，在这些细胞中，内源性长非编码RNA发挥着调节表观基因组的作用。参与小非编码RNA和长非编码RNA转录调控机制的蛋白质之间存在明显且共同的重叠，这表明早期使用小非编码RNA调节转录的研究利用了一种以前未被认识的RNA定向基因调控的内源性机制。在这里，我们通过回顾这些早期研究以及迄今为止获得的机制性见解，来综述非编码RNA在人类细胞转录调控和表观遗传基因沉默中所起的作用。我们还提供了一份已被证明受非编码RNA转录调控的哺乳动物基因列表。最后，我们探讨TGS如何可能作为未来治疗药物开发的基础。
