ABSTRACT
RNA interference, specifically, the use of small interfering RNAs (siRNAs), represents a new paradigm in gene knockout technology. siRNAs can be used to knock down the expression of a targeted transcript in what has been termed posttranscriptional gene silencing (PTGS). While there are a plethora of reports applying siRNA-mediated PTGS, there are apparent limitations such as the duration of the effect and saturation of the RNA-induced silencing complex. There is, however, recent data indicating that an alternative pathway is operative in human cells where siRNAs have been shown, similar to plants, Drosophila, Caenorhabditis elegans, and Shizosaccharomyces pombe, to mediate transcriptional gene silencing (TGS). Transcriptional gene silencing is operative by siRNA, or small antisense RNAs, targeting of the gene promoter regions, which results in epigenetic modifications that lead to silent-state chromatin marks and heterochromatization of the targeted gene. The observation that small RNA-directed TGS is operative via epigenetic
Overview ................................................................................................................405 21.1 Introduction ..................................................................................................406 21.2 Transcriptional Gene Silencing (TGS) in S. pombe .....................................406 21.3 TGS in C. elegans, Drosophila, and Neurospora ........................................407 21.4 TGS in Human Cells ....................................................................................409 21.5 Model of TGS in Human Cells ..................................................................... 410 21.6 Endogenous Small RNAs Involved in Gene Regulation .............................. 413 21.7 Conclusions ................................................................................................... 413 Acknowledgments .................................................................................................. 414 References .............................................................................................................. 414
modifications suggests that, similar to plants and S. pombe, human genes may also be able to be silenced more permanently or for longer periods following a single treatment. Undoubtedly, the potential to employ small RNA technology is broader than once envisioned. The potential to utilize small RNAs to direct epigenetic changes in local chromatin structure offers a new therapeutic avenue that could prove robust and of immeasurable therapeutic value in the directed control of gene expression.
