Uncovering the mysteries of long RNA molecules
Most cellular functions are carried out by proteins. The information for producing these proteins is encoded in DNA(opens in new window) that is transcribed into RNA molecules(opens in new window). However, only 1 % of the human genome(opens in new window) is involved in encoding protein sequences, with much of the remaining 99 % ‘noncoding’ regions of the genome being transcribed into long RNA molecules (lncRNAs). Researchers estimate that the human genome contains nearly 20 000 lncRNA genes, with many playing an important role in such biological processes as dosage compensation, transcriptional regulation, and establishing cell identity. They have also been implicated in diseases, including cancer and neurological disorders. Yet despite the large role they play, lncRNAs remain poorly understood. Working to fill this knowledge gap is the EU-funded and European Research Council(opens in new window) supported lincSAFARI(opens in new window) project. “Our aim is to better understand how these genome sequences have changed in the course of evolution, what kinds of functions they carry out, and how these functions can be efficiently interrogated in a lab setting,” says Igor Ulitsky, a researcher at the Weizmann Institute of Science(opens in new window) and lincSAFARI project coordinator.
A number of important discoveries
The project was based on the hypothesis that many lncRNA loci play key roles in gene regulation during cell differentiation(opens in new window). This hypothesis was tested using an interdisciplinary approach that combined computational, molecular and stem cell(opens in new window) biology. “Because this methodology was scalable, we were able to study completely uncharacterised long RNAs, eventually zooming in on their individual bases,” explains Ulitsky. “This allowed us to not only understand what functions lncRNAs play in key processes but, more importantly, how these functions can be leveraged to identify therapeutic targets and create drugs.” This methodology also led to a number of important discoveries. For example, researchers found a way to efficiently compare sequences of lncRNAs from different species, a process that allowed them to find very short regions that are functionally important. “We discovered an lncRNA that shows promise as a therapeutic target for a type of epilepsy(opens in new window),” adds Ulitsky. “We also found a previously unknown family of short RNA elements that dictate where the long RNA that contains them ends up in cells.”
Starting from scratch
According to Ulitsky, this project was particularly challenging as it required researchers to essentially start from scratch. “When we started, we knew nearly nothing about most of the genes we dealt with,” he notes. “But by the time the project finished we knew lots – including their function, how this function is related to specific physiological conditions and, in part, how these functions are carried out.” Researchers are now working to generalise these findings for the hundreds of thousands of lncRNAs that remain a mystery. “Thanks to the methods we developed during the lincSAFARI project, we no longer have to do this one-by-one but instead can do so in an efficient and streamlined process,” concludes Ulitsky. This research will form the bulk of the EU-funded lncIMPACT project.
