Chemical tags on brain RNA reveal the system shaping brain function

Researchers have mapped chemical tags on human brain RNAs in unprecedented detail – opening new paths to understand how regulation plays a role in conditions like schizophrenia and autism.

Genes determine many of our unique characteristics, from our eye colour to our health across a lifetime. They also help create the extraordinary complexity of the human brain.

DNA is like a master recipe book, full of thousands of recipes (our genes). To make all the things our bodies need, or to respond to immune challenges such as an infection, a temporary copy of the recipe is made, known as messenger RNA (mRNA). And just as a recipe can have variations in ingredients or instructions, so too can our genes produce mRNAs that carry different instructions.

“It’s like having different versions of a recipe for cookies – some with chocolate chips and others with icing,” explains Dr Mike Clark of the School of Biomedical Sciences’ Department of Anatomy and Physiology, whose research draws together genomics and neuroscience.

“And we know that our brain uses really different recipe versions to other parts of the body and even between different parts of the brain”.

The variety in mRNA recipes doesn’t stop there. In addition, parts of the mRNA can be chemically tagged along the way. These modifications can play an important role in controlling how much gene product gets made and how long the mRNA recipe lasts before it is discarded by the body. Chemical tagging of RNA is especially abundant in the brain and has been linked to learning, memory, and neurological diseases.

“Previously, it hasn’t been possible to work out which recipe versions the RNA modifications were added to,” Dr Clark says.

He and his colleagues have created the first detailed maps of chemical modifications across different mRNA versions in the brain. The team discovered over 57,000 modifications and revealed how these differ between mRNAs from the same gene and brain regions.

“For the first time, we were able to look directly at RNA in the human brain and see not just which genes were active, but the exact versions of those genes that were being used and how they were chemically modified. This was exciting because it has revealed a hidden layer of biology we simply could not see before.”

The mapping was achieved using cutting edge nanopore sequencing technology, which reads RNA molecules directly, to simultaneously decipher which RNA recipes were being produced and which parts were being modified. The team applied this method to post‑mortem human brain tissue from three distinct regions: the prefrontal cortex (involved in cognition and decision‑making), the caudate nucleus (important for motor control and motivation), and the cerebellum (which controls movement and contributes to cognition).

The researchers discovered each brain region had its own modification “signature”. The cerebellum showed the highest overall levels of modification, while the prefrontal cortex stood out for a different reason: it contained the largest proportion of previously unknown modification sites, many on genes involved in controlling behaviour and communication between brain cells.

Dr Josie Gleeson led the analysis of the team’s findings as part of her PhD candidature, supervised by Dr Clark and Dr Ricardo De Paoli-Iseppi, also from the School of Biomedical Sciences’ Department of Anatomy and Physiology.

The findings, published in Science Advances, show how RNA modifications are deeply embedded in helping to control the functions of brain regions, genes and their different mRNA recipes. By producing the first comprehensive maps of modifications on different mRNA recipes they also lay the groundwork for understanding how disruptions to RNA modifications play a role in neuropsychiatric or neurodevelopmental conditions like schizophrenia and autism spectrum disorder. In turn, the work could help develop new tests or interventions that target specific RNA or modifications.

“By identifying how RNA is modified with unprecedented resolution, we have created a map of modifications across the human brain that will enable discovery of the roles that specific modifications have in brain health and disease,” says Dr Clark.

Dr De Paoli-Iseppi adds that the work signals an important shift for researchers.

“Ultimately, our research shows that brain cells not only read genetic instructions but they actively edit and annotate them. Understanding this hidden layer of regulation will be crucial to understanding how the brain works and how neuropsychiatric and neurodevelopmental disorders arise.”

Lead image: composite via Scientific Advances/selvanegra/Getty/Canva