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Looking for the Missing Link in lncRNA Molecules

By Shelley Littin, iPlant Collaborative

Camelina sativa, an emerging bio-energy crop that is also replete with healthy omega-3 fatty acids, is one of the target species in which the researchers will analyze lncRNA interactions. (Image courtesy of Mark Beilstein/University of Arizona)

A research team will use the iPlant Collaborative’s big data management tools to unravel the secrets of little-understood lncRNA molecules, which may be involved in cellular regulation.

There is a theory that RNA, instead of DNA, is the original building block of all life. Yet many RNA molecules remain mysterious, their true nature and function little understood.

Now, with an award of over $2.5 million from the National Science Foundation’s Plant Genome Research Program, three scientists are setting out to study the true nature of a class of mysterious RNA molecules known as lncRNA.

Long non-coding ribonucleic acid molecules, or lncRNA, are a large – and largely understudied – group of RNAs that do not provide genetic code for proteins, as RNA initially was understood to do.

Instead, these strange molecules appear to function in numerous biological processes at the cellular level, oftentimes affecting tissues in many organisms.

“About 50 years ago the idea emerged that the first molecule of life was RNA, before DNA and before protein.” Eric Lyons is an assistant professor in the University of Arizona’s College of Agriculture and Life Sciences and BIO5 Institute.

“RNA was discovered to be able to not only carry genetic information, but also to catalyze biochemical reactions. It’s similar to DNA, but it’s more flexible.” DNA molecules only carry genetic information, and are not known to work on cellular processes at all. Lyons explained that its flexibility allows RNA to adopt more complex structures – and hence more diverse functions – than DNA.

“RNA isn’t just this intermediary of genetic information flowing from the genome into proteins. RNA has a huge role in the regulation of nearly all cellular processes, including the activity of individual genes, chromosomes, and whole genomes.”

“This is an under-appreciated class of genetic elements,” said Mark Beilstein, also an assistant professor in the School of Plant Sciences at the UA’s College of Agriculture and Life Sciences. “While the field of genetics has focused in large part on the functions of genes, investigations into the biology of lncRNA molecules are just now gaining steam. Uncovering the functions of lncRNA molecules is an important next step in elucidating how information flows from genomic DNA to RNA and proteins responsible for carrying out the work of the cell.”

The NSF grant will enable the researchers to investigate lncRNA functions in several different plant species, seeking to identify and classify the molecules and to understand their roles in plant cellular processes.

Different lncRNA molecules are genetically expressed at different times in a plant’s life cycle, including in response to stressors such as drought or soils with high salt content, Lyons explained. We want to know whether plants under stress make lncRNA molecules to redesign the plant’s gene expression program in response to that stress, he said.

If the researchers can untangle the functions of lncRNA, Lyons said, “it could have huge economic implications for how we could modify plants to be better suited to survive different environmental stresses. As we begin to understand the importance of the regulation of the cell by RNA, we start to see our world expand immensely.”

Scientists visualize RNA-protein interaction data using EPIC-CoGe, a program developed in collaboration with the iPlant Collaborative. (Image courtesy of Eric Lyons/iPlant Collaborative)

The research project is expected to take four years, over the course of which, “we hope to gain a greater understanding of this potentially important class of molecules, their biology, and their function in the cell nucleus,” said Brian Gregory, an assistant professor of biology at the University of Pennsylvania and a leading expert in RNA regulation of cellular processes.

Gregory will use a new technique developed in his lab called PIP-seq to isolate lncRNA molecules from the nuclei of plant cells, and visualize genetic material that has never been observed before.

Mark Beilstein, a comparative evolutionary biologist at the University of Arizona, will unravel and identify the different groups of lncRNA molecules as they are isolated from the study plants. The inter-relation of the lncRNA may give clues to help the scientists understand how the molecules have evolved their current structure and function.

Lyons, who in addition to his role at the UA is also co-principal investigator of the iPlant Collaborative, will provide for the team’s data management.

The iPlant Collaborative is the pre-eminent NSF-supported project to develop scalable infrastructure for the life sciences. The research team will leverage iPlant’s big data storage and computational support for the array of genetic information they will collect as they identify lncRNA molecules.

“We’re going to need scalable data management, visualization, and analysis platforms to organize data and make it broadly available to the wider research community,” Lyons said. The final dataset will be integrated with publicly available data, opening the doors for future science discoveries.

Throughout the project, teams of post-doctoral researchers will rotate through the three research environments and work with each of the three scientists to learn how different specialties of science help advance discoveries beyond the potential of any one scientific field. “That hybrid of skills and ability to communicate readily across different team environments will be essential for the next generation scientific workforce,” said Lyons.

The researchers also will instruct a class at both the UA and University of Pennsylvania, involving the students in real scientific discovery by teaching them how to assist with the project’s data analysis.

“This project is a great example of people coming together around iPlant core technology, building extensions that answer one need but that are in turn used as foundations for other endeavors,” Lyons said.