RNA and transcriptional modulation of gene expression

Abstract

The roles that RNA molecules play in the regulation of gene expression have only recently begun to come to light. Recent work in this area has uncovered several complex, RNA-mediated networks of gene regulation in eukaryotic systems. One newly discovered mechanism of RNA mediated gene regulation takes place at the level of transcription. In yeast, plant, and mammalian systems, small RNAs targeted to gene promoters can result in a repression of transcription. Small RNA mediated transcriptional silencing has been shown to be operative by changes in chromatin structure at the targeted promoter. Specifically, silencing has been observed to correlate with decreases in certain active-state histone modifications, increases in various certain-state histone methylation marks, and in some instances, DNA methylation at the targeted promoter. These epigenetic remodeling events represent a more stable, heritable form of gene regulation as opposed to the transitory post-transcriptional regulation observed in traditional RNAi mechanisms. Several recent findings have shed light on this newly discovered link between small RNA molecules and epigenetic regulatory machinery, notably in human cells.

Figure 1

Putative models for small RNA directed TGS in human cells. (A) The RNA/RNA model of transcriptional gene silencing is shown where the antisense strand of the small RNA either binds or associates with Ago-1 and possibly Ezh2, DNMT3a or HDAC-1 and then localizes to the elongating RNAPII expressed transcript that spans the targeted promoter loci. This model is supported by data showing that RNAPII activity and a low copy promoter associated RNA is involved in small RNA directed TGS in human cells., Alternatively, or more common at TATAA loci and transcriptional start sites the RNA/DNA model may be operative. (B) In the RNA/DNA model the antisense strand of the small RNA may localize with the transcriptional silencing complex containing Ago-1, Ezh2, DNMT3a and HDAC-1 to the genomic DNA. The localization of these components to the transcriptional start site might alter later RNAPII binding and activity. This model is supported by data showing transcriptional start sites are susceptible to small antigene RNA targeting.