The site in the brain where RNA is edited

Mount Sinai researchers have cataloged thousands of brain sites where RNA has been modified over a human lifetime, a process known as adenosine to inosine (A-to-I) editing, providing important new avenues
for understanding the cellular and molecular mechanisms of brain development and how they affect health and disease.

In a study published in Cell Reports, the team describes how the rate of RNA editing in the brain increases as individuals age, with implications for analyzing the pathology of A-to-I editing alterations across a range of neurodevelopmental and aging disorders
.

Dr.
Michael S.
Breen, assistant professor of psychiatry, genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai and a member of the Sewell Center for Autism Research and Treatment, said, "Our work provides more nuanced and accurate insights
into contributions to RNA modifications during human brain development through A-to-I editing.
The field has identified millions of A-to-I sites in the brain, making it particularly challenging
to determine which of them may be physiologically important.
We narrowed the scope down to about 10,000 sites with potential functional roles
from early fetal development to advanced aging.
By providing an atlas of these sites, we have opened the door to further understanding of brain neurodevelopment through A-to-I
RNA modifications.
”

DNA holds the genetic blueprint of humans and other organisms, but RNA actually executes instructions to create functional proteins
.
Modifications accumulated on RNA can alter the eventual function of
a protein.
The ADAR enzyme family introduces these individual A-to-I variations
.
During early fetal development, a small number of edits play an important physiological role
by regulating synaptic transmission and neuronal signaling in the brain.
The study suggests that RNA in the brain accumulates thousands of individual edits over the course of a human lifetime, and that these changes are likely to have functional consequences
as we age.

Mount Sinai's study generated and compiled RNA sequence data
from the brains of more than 800 people.
The data covers all stages of prenatal and postnatal development, from the earliest embryonic progenitor cells to the uniquely functioning brain tissue
of centenarians.
This extensive study has allowed the researchers to develop a model that describes, for the first time, how A-to-I editing evolves over the course of
a lifetime.
In this model, unedited RNA is expressed during fetal development and may be translated into proteins, while edited RNA is more abundant
in the adult brain.

"This means that at older ages, A-to-I edits are generally edited at a higher rate and frequency, including stabilizing RNA structures and regulating the way
RNA interacts with microRNAs," Dr.
Brin noted.
His team also learned that a subset of these A-to-I sites introduces new amino acid substitutions into protein-coding regions of the brain, an event known as RNA recoding
.
This is a particularly important finding because RNA codes have a direct functional and/or structural impact on
proteins.

The Mount Sinai team also sought to answer the question of how genetic variation might explain some of the differences
in A-to-I editing as individuals age.
They learned that because editing sites are strongly regulated during early fetal development, there are significant differences
in editing levels across thousands of sites based on unique genetic variations.
This distinction gradually disappears
during development after birth.
From a basic scientific perspective, the dynamic regulatory sites discovered by the researchers provide many avenues
for future fundamental mechanisms for manipulating early brain development through A-to-I editing.

Brin's lab research interests include functional genomics, computational biology, and neuroscience, and his previous research has found that A-to-I editing is disrupted in brain tissue in individuals with neurodevelopmental disorders
.

"This work provides us with a direct way
to analyze the pathological effects of A-to-I alterations in a range of neurodevelopmental and aging disorders," he said.
It is now clearer than ever that elucidating the dynamic regulation of RNA editing could provide unique insights
into their role in promoting health and disease.
”

Winston H.
Cuddleston, Xuanjia Fan, Laura Sloofman, Lindsay Liang, Enrico Mossotto, Kendall Moore, Sarah Zipkowitz, Minghui Wang, Bin Zhang, Jiebiao Wang, Nenad Sestan, Bernie Devlin, Kathryn Roeder, Stephan J.
Sanders, Joseph D.
Buxbaum, Michael S.
Breen.
Spatiotemporal and genetic regulation of A-to-I editing throughout human brain development.
Cell Reports, 2022; 41 (5): 111585