Duke researchers published a breakthrough in understanding m6A through the development of a genetically encoded sensor for the most abundant internal mRNA modification.
These mRNA modifications are “critical regulator[s] of gene expression and cellular physiology.” By programming cells to couple m6A modifications with the expression of certain observable proteins, this breakthrough presents possibilities for new research on how m6A affects various diseases and how to create therapeutics for them.
“This idea was first conceptualized back in 2019,” Assistant Professor of Biochemistry Kate Meyer said. “But moving from an idea to a functional, even just initial prototype is often easier said than done.”
Led by Fadi Marayati, a postdoctoral associate in The Meyer Lab, the research team hopes that their work can open doors to therapeutic implications. According to Meyer, the m6A modification in cells is important for the expression of proteins linked to many types of cancers such as acute myeloid leukemia and glioblastoma, as well as immune, neurological and cardiovascular diseases.
“The tools that we have to see and study how it might be dynamically regulated largely require isolating the RNA from the cell,” Meyer said. “We needed a way to look at how m6A is changing in living cells, and so we really wanted to fill that gap.”
The m6A sensor technology accomplishes this goal by expressing observable fluorescent proteins when m6A is deposited on mRNA, allowing researchers to observe changes in m6A and improve their understanding of its effects.
The sensor’s ability to be inserted into a versatile selection of genomes also enables its use in a variety of cell types, including living organisms. This makes the sensor an attractive choice for future studies.
The Meyer lab is still exploring various improvements such as making the m6A sensor smaller, more efficient and more precise. The current system involves a protein that edits multiple types of RNAs near the cell. Editing of RNAs that are not coupled with m6A modifications can lead to detrimental, long-term effects for the cell.
The research team is replacing that protein with a CRISPR/Cas-based approach, leveraging the precise targeting power of CRISPR to recruit the protein to the correct reporter RNA.
“I think that will open up more doors to using this in different biological systems without perturbing the natural state of the cell,” Meyer said.
The research team is also exploring possibilities that arise from using other observable proteins instead of fluorescent proteins.
“That's a nice application because it makes it a very programmable and very versatile system, but it can let us do things like overexpress a tumor suppressor protein in a cell that might have high levels of m6A,” Meyer said. “And so we're further developing that as well to potentially use this platform as a novel therapeutic strategy.”
Although they are expecting future iterations of the sensor, the team still considers the creation of the functioning sensor prototype as a thrilling moment.
“We hope that this tool will be really useful for other labs who study m6A,” Meyer said. “And we're excited about the future of this technology.”
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Winston Qian is a Pratt first-year and a staff reporter for the news department.