RNA de-inhibition

Small RNAs are famous for their gene-silencing ability. But new results from Tomoko Kuwabara, Fred H. Gage (Salk Institute, La Jolla, CA), and colleagues show that some tiny RNA species turn genes on, not off.Figure NRSE dsRNA (red) makes NRSF/REST (green) an activator in differentiating neurons.This new class of RNAs is needed to make neurons. “Small double-stranded RNAs exist in reasonably high concentrations in cells that have just committed to neuronal lineages,” says Gage. These RNAs are homologous to a promoter sequence called NRSE/RE-1, which is found in a wide range of genes that are expressed only in neurons. In other cell types, these genes are known to be shut off by the NRSF/REST repressor. The group shows that this repressor becomes an activator when NRSE dsRNAs are around. As a result, neuronal genes are turned on, and multipotent adult neural stem cells become neurons. The NRSF/REST protein binds strongly to the dsRNA, and the two probably sit on promoters as a complex. When both are present, histone acetylases and chromatin-remodeling proteins replace the deacetylases and methyl-DNA binding proteins that are found at neuronal gene promoters when only NRSF is expressed. The dsRNAs are found in regions of the hippocampus where neurons are differentiating, and their destruction prevents cultured cells from becoming neurons in response to inducing signals. A single molecule RNA switch that creates an entire lineage may not, however, be found outside neurons. “It's an unusual case,” says Gage, “because of NRSF. It binds to so many promoters that it makes the RNAs generalizable.” ▪ Reference: Kuwabara, T., et al. 2004. Cell. 116:779–793. [PubMed]