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 more than $2.5 million from the National Science Foundation’s Plant Genome Research Program, the University of Pennsylvania’s Brian Gregory will join two scientists from the University of Arizona to study the true nature of a class of mysterious RNA molecules known as lncRNA.

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 Gregory, an assistant professor of biology in Penn’s School of Arts & Sciences 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 to visualize genetic material that has never been observed.

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,” said Eric Lyons, an assistant professor in the University of Arizona’s College of Agriculture and Life Sciences, who is part of the team. “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 but are not known to regulate cellular processes. Lyons explained that RNA’s flexibility allows it 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,” he said. “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 underappreciated class of genetic elements,” said Mark Beilstein, third team member and also an assistant professor in the School of Plant Sciences at 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,” Lyons said.

If the researchers can untangle the functions of lncRNA, he 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.”

Beilstein, a comparative evolutionary biologist, 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 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 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 Penn and UA, involving the students in real scientific discovery by teaching them how to assist with the project’s data analysis