Making the silent genes speak

In their study of genomes, researchers have long focused attention on specific areas such as genes that carry instructions for making proteins. Meanwhile, they’ve neglected a crucial set of genes that don’t code for proteins — instead these genes code for so-called long non-coding RNA (lncRNA) and play an important role in the regulation of protein-coding genes.

Researchers now realize that these RNAs play a pivotal part in regulating genes, yet they have not been extensively studied. Now a team of researchers from Saudi Arabia and the United States has used recent advances in computational biology to look closely at the genes that carry instructions for lncRNA.

Led by Vladimir Bajic, the director of the Computational Bioscience Research Center at KAUST, the research team discovered that the lncRNA are regulated quite differently from protein-coding genes.

“While we did expect that these two large gene groups could be controlled in different ways, we did not expect such a radical difference in their regulation,” says Bajic. “The results suggest a whole new set of possibilities for the control of gene activities.”

For instance, such knowledge could help scientists in the field of synthetic biology to create cells with regulatory switches that can alter the expression of lncRNA but don’t interfere with control of a cell’s protein-coding genes. This could underpin new gene therapies for diseases such as cancer and neurological disorders.

Each gene—whether it codes for a protein or just production of a piece of gene-regulating RNA—has a region of DNA, known as the promoter, located near the transcription start site which helps initiate the process of turning the gene into an RNA transcript.

Bajic and his team are the first to perform an extensive study of promoters of lncRNA. Using a series of computational approaches, they undertook a genome-wide comparison of promoters of human lncRNA and protein-coding genes.  They found several distinct differences in a range of characteristics, including the DNA sequences of the promoters and the occurrences of transcription factor binding sites. The researchers suggest some of these transcription factors hold the key to regulating lncRNA without affecting other RNA involved in protein synthesis.

A broader implication from this research is the need to rethink approaches to understanding gene activity by incorporating lncRNA genes into the relevant databases used by biologists. “Rethinking lncRNA will help us understand how genes activate and improve our capacity to control this activation in future,” Bajic says.

References

1. Alam, T., Medvedeva, Y.A., Jia, H., Brown, J.B., Lipovich, L. & Bajic, V.B. Promoter analysis reveals globally differential regulation of human long non-coding RNA and protein-coding genes. PLOS ONE 9, e109443 (2014). | article