title: Transcriptional gene silencing in humans.
abstract: 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.
authors.affiliation: 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.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Weinberg
authors.affiliation: 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 kmorris@scripps.edu.
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Morris
mesh_terms: D000818:Animals; D002460:Cell Line; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006801:Humans; D008322:Mammals / Q000235:genetics; D008954:Models, Biological; D016372:RNA, Antisense / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D016372:RNA, Antisense; D062085:RNA, Long Noncoding