Researchers in Sweden Develop Tools For Determining Functions of Junk DNA

Researchers at Karolinska Institutet in Sweden have developed high-precision tools for identifying the functions of the genetic sequences that do not code for protein production. Such genes, called non-coding or “junk” DNA, make up the majority of the human genome but are harder to study than their protein-coding counterparts. Recent research has shown, however, that some of these sequences can give rise to RNA that affect vital cellular processes, and many diseases are linked to genetic changes in these noncoding regions.

“This has come as a great surprise and we now need to understand in detail how these genetic changes affect different diseases in order to eventually be able to develop more accurate drugs,” says the study’s first author Per Johnsson, researcher in Karolinska Institutet’s Department of Cell and Molecular Biology. “Generally speaking we don’t know that much about this interaction, but we believe that noncoding RNA will one day be a source of attractive drug candidates. It’s therefore extremely important that we speed up the characterization of these RNA molecules.”

For this study, the researchers combined single-cell sequencing with mathematical calculations to identify the function of noncoding RNA. Using these tools, they were then able to identify an entirely new mechanism for how the RNA molecules regulate the activity of protein-coding genes in their vicinity.

“Exploiting heterogeneity in asynchronously growing cells, we identified and experimentally validated lncRNAs [long noncoding RNAs] with cell state-specific functions involved in cell cycle progression and apoptosis,” according to the paper. The team also identified cis-functioning lncRNAs and showed that knockdown of these lncRNAs modulated the nearby protein-coding gene’s transcriptional burst frequency or size.

“After many years of development, single-cell sequencing has now reached a stage where we can isolate individual cells and study regulating mechanisms with high precision,” says principal investigator Rickard Sandberg, professor at the Department of Cell and Molecular Biology, Karolinska Institutet. “This is multidisciplinary research that we believe will contribute significantly to our basic understanding of cell biology and that, in the long run, can give us new insights into how cellular function can be influenced through the agency of small drug substances.”

The group has so far used the method to study the function of a handful of noncoding RNA molecules, but there are thousands of similar molecules waiting to be characterized. They now plan to do similar work on RNA molecules with a possible role in the development of disease, such as cancer. “We’ll be applying larger-scale methods to study hundreds to thousands of similar genes in parallel, thus­ greatly advancing our understanding of these interesting RNA molecules,” says Dr. Johnsson.

The paper, entitled “Transcriptional kinetics and molecular functions of long noncoding RNAs,” was published recently in Nature Genetics.