New map of mRNA variations captures inner workings of brain | Cornell Chronicle

Researchers at Weill Cornell Medical College have assembled the most comprehensive map to date of messenger RNA (mRNA) variation in the mouse and human brain. The atlas is an important new resource for neuroscientists to understand how the brain develops, how different neurons specialize, and more generally function.

RNA transcripts, copied from DNA sequences, carry instructions for building proteins and show which genes are active in a particular cell. When a gene is copied into the original RNA transcript, it can often be processed differently to form different splice variants or isoforms; therefore, a single gene can produce several different proteins. Although this complex layer of biology is thought to hold the key to understanding many other mysterious diseases, particularly in the brain, it has been a huge technical challenge.

In a study published April 9 in the journal Nature Neuroscience, researchers used cutting-edge sequencing methods to record the mRNA isoforms expressed in different brain regions, different cell types and different growth stages in mouse and human brains. They found that, even within a given cell type, the isoforms of certain genes vary greatly depending on where the cell is located and the stage of brain development.

“This is definitely a big step forward that allows us to now be more Examine brain processes in detail.

First author Anoushka Joglekar is a doctoral student who worked in Tilgner’s laboratory during the research and was co-supervised by Dr. Elizabeth Ross, the Nathan E. Cumming Professor of Neurology and Neuroscience at Weill and director of the Center for Neurogenetics. . Joglekar is now a postdoctoral fellow at the New York Genome Center, a research institute co-founded by 14 New York academic institutions including Weill Cornell Medical College.

Isotype variation is part of the fine print of biology, making it inherently difficult to read. This is primarily because standard RNA sequencing techniques cannot reliably detect differences between mRNA isoforms. To solve this problem, researchers turned to more expensive and time-consuming long-read sequencing, which still requires extensive data processing to achieve sufficient accuracy. They accomplished this difficult task by recording the single cells that produced each long-read RNA sequence. This allowed the researchers to identify isoforms from hundreds of thousands of mouse and human brain cells.

The resulting atlas, based on data sets from smaller studies conducted by the same team in 2018 and 2021, will serve as a fundamental reference for neuroscientists studying normal and abnormal brain function and development. But the team’s preliminary analysis of the data also yielded some surprising results, which will be followed up in future investigations.

For example, the researchers found that for many genes important for signaling between neurons, the same cell type expresses different mRNA isoforms in different brain regions. Variation is more pronounced during adolescence when many subtypes exhibit unexpected patterns of fluctuations.

We see some of these isoforms switching on and off throughout development until they stabilize in adulthood, Joglekar said.

The team also observed that in previous genetic studies, many genes with highly variable isoforms have been linked to major brain diseases, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and bipolar disorder. , anxiety disorders and depression.

Although most of the findings were similar in mouse and human brain cells, the researchers plan to emphasize human cells in future studies, such as comparing subtype variations in normal aging and aging-related brain diseases.

This work was supported in part by the BRAIN Initiative Cell Census Network and the National Institute of General Medical Sciences.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with outside organizations to promote scientific innovation and provide expert guidance. The agency makes these revelations public to ensure transparency. For this information, see Tilgena’s profile.

Jim Schnabel is a freelance writer at Weill Cornell Medical College.