Researchers at the University of Kentucky and Hebrew University in Jerusalem are partnering to study the complexity of the human brain. Specifically, researchers will test whether new, so-far unknown proteins exist in the brain.

Labs from the two institutions have obtained a joint grant from the National Science Foundation (NSF) and the United States-Israel Binational Science Foundation (BSF) to study new aspects of RNA biology.

Researchers are working to answer a fundamental question: Why do humans have more complex brains than other organisms with roughly the same number of genes?

As part of the more than $700,000 grant, Stefan Stamm, Ph.D., a professor in the molecular and cellular biochemistry department in the UK College of Medicine, and his lab are studying the characterizations of the proteins and looking at their biological implications.

Stamm’s lab is partnering with Ruth Sperling, Ph.D., professor (emeritus) in the Department of Genetics at the Alexander Silberman Institute of Life Sciences of the Hebrew University of Jerusalem. She is an expert in RNA processing.

RNA is the mediator in turning instructions held in your DNA into proteins in your cells. During the process, RNA is heavily modified with pieces cut out, or spliced, and put back together in a new line of RNA. Sometimes those pieces form in circles, creating circular RNA.

“We propose that there's a new set of proteins that have not been identified or looked at in the human brain that are encoded by the circular RNAs, and they fulfill novel functions in cells,” said Stamm.

Circular RNAs are mostly found in the brain and their formation is promoted by genomic elements specific to humans and other primates, called Alu-elements. The human genome consists of about 11% Alu-elements and their expansion in primates correlates with brain complexity.

The research teams will test the hypothesis that primate-specific circular RNAs are translated into proteins after the molecules in the circular RNA undergo an epigenetic change.

“Do circular RNAs encode proteins? Are these proteins functional? Can you find them in brains?” said Stamm. “That’s what we’re analyzing. It’s never been looked at.”

Researchers propose the new proteins made from those specific circular RNAs strongly increased molecular complexity in the brain, which could enhance brain functions.

“If we have new proteins, we have a completely new proteome that has new functions and can contribute to the human brain,” said Sperling. “This has wide implications. For example, you can look for genetic modifiers. Are there genetic modifiers that correlate with schizophrenia, epilepsy, autism or neurological disease?”

Sperling’s lab will focus on understanding how circular RNA are made by the splicing machinery in cells. Together with Joseph Sperling, Ph.D., she discovered and characterized the endogenous splicing machine in mammalian cells. Recently, her team identified circular RNA within the endogenous splicing machine. Her team will use this system to study whether RNA is spliced or backspliced, forming linear and circular RNAs, respectively, when that occurs, and how it’s regulated in the brain.

“These proteins are not very abundant, but they could form or modify catalytic functions in other proteins. So, if you want to understand the brain you have to look at these molecules,” said Stamm.

As part of the three-year project, there will be annual two-week RNA biology courses held in the summer at Hebrew University in Jerusalem led by Stamm and Sperling. Students from both universities will have theoretical lectures and do hands-on experiments during the course.

Research reported in this publication was supported by the National Science Foundation under Award Number 2221921. The opinions, findings, and conclusions or recommendations expressed are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.