EpiGenie recently reviewed the epigenetic text RNA and the Regulation of Gene Expression by Kevin Morris. To give you a small taste of the material covered in the book, here is a summary of one of the chapters:
Small RNA-mediated Gene Activation
by Long-Cheng Li
Noncoding RNAs (ncRNA) which, by definition, do not code for proteins, are estimated to make up ~98% of the human transcriptome. Once thought to be the transcriptional by-product of “junk DNA,” ncRNA is rapidly becoming recognized as an important mechanism of gene regulation. Small double-stranded RNAs (dsRNA) in particular have been extensively studied in the context of gene silencing by a mechanism commonly referred to as RNA interference (RNAi). This chapter focuses on the lesser known flip-side of RNAi, which involves small dsRNA-mediated gene activation (RNAa).
Known functions of ncRNA
Noncoding RNA can be divided into 2 major functional classes: 1) housekeeping ncRNAs and 2) regulatory ncRNAs. Well-studied housekeeping functions include those involved in RNA splicing, editing, and protein synthesis. More recently discovered housekeeping functions of ncRNA involve serving as reaction catalysts (ribozymes) and molecular sensors (riboswitches). The regulatory functions of ncRNA, on the other hand, directly impact gene expression through a variety of mechanisms. While large regulatory RNA (hundreds to thousands of nucleotides long) are known to participate in diverse processes such as dosage compensation and imprinting, the focus of this chapter is on small regulatory dsRNA with a size range of 20-30 nucleotides.
Small dsRNAs as negative regulators of gene expression
RNA interference by exogenous dsRNA was first reported in Caenorhabditis elegans in 1998. Subsequent studies showed that small endogenous dsRNA, called microRNA (miRNA), also participate in RNAi in a trans-acting, target sequence-specific manner similar to that reported for exogenously introduced small interfering RNA (siRNA). While the mechanism of miRNA-mediated gene suppression has now been elaborated with respect to the proteins involved and RNA processing, the relationship between RNAi and long-term suppression of gene expression through RNA-directed DNA methylation (which has been observed in plants) or other epigenetic mechanisms is still unknown.
dsRNA-induced transcriptional activation
In contrast to RNAi, RNA activation (RNAa) mediated by small activating RNAs (saRNAs) is a relatively recent (2006/2007) discovery. Like RNAi, RNAa targets specific genes by sequence complementarity, with target specificity determined primarily by the 5’-end of the saRNA molecule. However, the time course of RNAa is very different from that of RNAi, with induction of gene expression occurring 2-3 days post-transfection as opposed to several hours for RNAi-mediated suppression, and the effects of RNAa appear to be longer lasting (at least 10-15 days vs. 5-7 days for RNAi). The reasons for these differences in time course are not clear, but it has been postulated (based on some evidence) that the slow induction reflects the time required for saRNA to gain access to DNA (possibly occurring only during mitosis), and that the prolonged effects on gene expression may be due to longer-lasting RNAa-induced epigenetic changes in chromatin. Given that expression of rare transcripts can be increased 5- to 10-fold, RNAa can be a potent mechanism for altering gene expression and restoring function of silenced genes.
miRNAs and bidirectional gene regulation
MicroRNAs are small endogenous ncRNA that are produced by the elaborate processing of longer precursor RNA molecules. While much of the attention regarding miRNA has focused on its role in the inhibition of gene expression, the activation of gene expression in response to miRNA has been generally overlooked as a secondary effect. In light of what recent studies on saRNA have shown, it would be of utmost importance to further investigate the potential role of miRNA in gene activation.
Future of small RNA Gene Activation
The recent discovery of RNA activation by small dsRNA raises the exciting possibility that genes silenced by disease might be turned on again in a gene-specific manner by saRNA. However, much more work needs to be done to first understand the mechanism and limitations of dsRNA-mediated gene activation before saRNA can be applied therapeutically. Together, the phenomena of RNAa and RNAi demonstrate the complexity as well as yin-yang nature of gene regulation by small double-stranded ncRNA.
**This chapter summary was provided by Valerie Hu, Ph.D. who is a Professor in the Department of Biochemistry and Molecular Biology at The George Washington University Medical Center.
You can get your own copy of RNA and the Regulation of Gene Expression at the Horizon Press website.