$2.3M grant will help U-M researcher define ‘RNA alphabet’


University of Michigan pediatric neurologist Vivian Cheung is launching an international project to identify the full range of RNA building blocks inside human cells.

The effort, supported by a new $2.3 million grant from The Warren Alpert Foundation, aims to lay the groundwork for a comprehensive “human RNome” project, similar to the Human Genome Project completed in 2003.

Vivian Cheung
Vivian Cheung

The Human Genome Project mapped the DNA in human cells by determining the order of the four bases that form the building blocks of DNA (adenine, cytosine, guanine, and thymine). The result was a genetic code, the instructions for operation embedded inside each human cell.

Scientists are now pushing for a second sequencing project to map the RNA in human cells, and the idea is gaining momentum at the national level.

“Particularly in the last three years, in the face of a global pandemic caused by an RNA virus, it has become extremely clear that we need a way to accurately sequence RNA,” said Cheung, Frederick G. L. Huetwell Professor of Pediatric Research and professor of pediatrics and of human genetics at the Medical School, and a research professor at the Life Sciences Institute.

“To do that, we first need to identify the actual building blocks that comprise the sequence. But right now, we don’t even know what all the building blocks are.”

To produce the proteins that keep all cells — and organisms — functioning, DNA is first transcribed into RNA, and then RNA is translated into the appropriate type and quantity of proteins.

“Along with DNA, the genetic code, RNA as the regulatory code provides cells with instructions to handle the enormous number of needs within a body,” Cheung said. “RNA is very complex because it needs to supply the necessary regulation.”

This extended information comes in the form of hundreds of chemical modifications to add to the basic building blocks of RNA (adenine, cytosine, guanine, uracil), allowing precise regulation of cellular functions in response to the organism’s ever-changing needs.

“These chemical decorations are functionally part of the spelling of the RNAs, so each one has its own unique function and is part of the comprehensive RNA alphabet,” Cheung said. “That means we have the potential for hundreds of individual functional building blocks that need to be identified and defined.”

Her lab at the Life Sciences Institute is working with collaborators at the Massachusetts Institute of Technology, the University of Cincinnati and the Institute of Molecular Biology in Mainz, Germany, to do just that.

With funding from The Warren Alpert Foundation, the researchers plan to first establish explicit protocols for extracting and preparing RNA for potential sequencing, and then use mass spectrometry to determine which components are in the RNA from different human cells.

The results, they hope, would establish the foundational data that complement a report being developed by the National Academies of Science, Engineering and Medicine to launch a full Human RNome Project, sequencing human RNA.

In addition to Cheung, the work will be led by Peter Dedon of MIT, Mark Helm of the Institute of Molecular Biology and Patrick Limbach of the University of Cincinnati.


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