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.

A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers

“…Our result suggest that altering the sequence, structure and, therefore, function of paRNAs provides an additional and still unexplored way by which polymorphic sites and somatic mutations in noncoding regions influence the epigenetic landscape and impact on human disease. These results also support the development of inhibitors targeting these ncRNAs for gene-selective transcriptional reprogramming28346061, since knockdown of S-paRNA reactivates CDH1 expression in prostate cancer cells and impairs their proliferative, clonogenic and stem-likeness. Reprogramming transcription of individual genes through this approach would have broad implications for epigenetic therapy of cancer and other diseases.…”

Roles of MicroRNA across Prenatal and Postnatal Periods

“…These alterations include lower proliferation, impaired migration and angiogenic capacity, as well as increased apoptosis [24]. Alterations of noncoding RNA, including miRNA, are implicated in persistent and long lasting epigenetic changes, that can be transferred during cell division [63], and that are associated with cell dysfunction and disease [24,63]. In diabetic conditions, the prolonged exposure to hyperglycemia generates a long-lasting impression on vascular cells and the progression of vascular complications [64], leading to the ‘glycemic memory’ theory that explains how chronic hyperglycemic conditions lead to persistent outcomes, through epigenetic changes [65] and miRNA alterations [64].…”

“…Where miRNAs are found to target epigenetic regulators the effect on the recipient target can be persistent and durable [24,63]. miR-148-3p, one of the most highly expressed miRNAs in human milk [75], targets the DNA methyltransferase 3b, a key component of the epigenetic machinery during development [95] and an essential DNA methyltransferase in the intestinal epithelium [96].…”

Gene and virotherapy for hematological malignancies

“…Discovery of the pervasive regulatory functions of small RNA molecules in transcriptional gene silencing, epigenetic modification and chromatin structure, and chromosomal segregation provide new potential therapeutic applications for RNAi [26, 27]. Recent advances in chemical modification of RNA molecules, such as with 2’OMe RNA, extends siRNA stability from several minutes up to 24 hours when exposed to serum ribonucleases [28].…”