| Genes that react to cellular sugar content are regulated by a long non-coding RNA via an unexpected mechanism.|
By Sabrina Richards | May 1, 2012
EDITOR’S CHOICE IN GENETICS/GENOMICS
Long noncoding RNAs (lncRNA) look like messenger RNA, with a 5’ cap and poly-adenylated tail, though it’s a mystery why they go untranslated. LncRNAs inhabit what Bernhard Dichtl, an RNA researcher at Deakin University in Australia, calls a “shadow world of gene expression.” Although their function is still not fully understood, they often appear to be involved in repressing gene transcription.
Many lncRNA codes are situated in the same location as the genes they repress, but on the opposite strand, such that their codes run in the reverse direction. Transcription of lncRNA code is thought to repress gene expression by blocking transcription factors or recruiting chromatin remodeling proteins. This would suggest that the lncRNA message itself is superfluous to its function as a repressor. But that idea didn’t quite make sense to Sarah Geisler, who studies RNA turnover in Jeff Coller’s lab at Case Western Reserve University in Ohio. Why then would these transcripts have a 5’ cap and polyadenylated tail, which help keep mRNA from being degraded?
Geisler looked at a strain of yeast that could not remove its guanosine cap, and noticed it had high levels of lncRNA. This suggested that lncRNA stability is regulated by its cap, and therefore that the lncRNA transcript itself might have a regulatory function.
Many of the lncRNA sequences were located near inducible genes, including those in the GAL family, which are turned on, turned off, or ignored when yeast responds to changes in the sugar environment. The DNA for one such lncRNA was coded on the matching strand of the DNA encoding GAL10 and the neighboring GAL1 gene.
Then Geisler and colleagues shifted the yeast that retained their lncRNA transcripts to a galactose-rich environment, which would normally induce GAL10 and GAL1 transcription. However, the researchers observed a drop in the number of GAL1 mRNA transcripts, suggesting that the lncRNA message—not simply the gene—repressed GAL1 mRNA transcription. In wild-type cells, galactose prompted histone acetylation—and thus release of histone bundling—at the GAL1 locus, but not in cells where the lncRNA remained stable. This implies that lncRNA may regulate how easily these inducible genes respond to environmental changes, Geisler says.
The finding revealed a surprising new layer of GAL regulation. “After 50 years, we didn’t think there was anything else to learn” about GAL, says Coller.
In addition, decapping machinery turns off during development, suggesting that regulation via lncRNA may play an important role in early gene regulation.
S. Geisler et al., “Decapping of long noncoding RNAs regulates inducible genes,” Molecular Cell, 45:279-91, 2012.