A new study has revealed that a long non-coding RNA plays a far more extensive role in regulating gene expression than previously understood, according to findings published in Nature Communications.
Long non-coding RNAs (lncRNAs) are RNA molecules that do not encode proteins, which led to their dismissal by many scientists as unimportant as it relates to DNA processes. For years, laboratories lacked the tools to study these molecules, and their roles in cellular processes remained obscure. However, the new study demonstrates that lncRNAs are far from inert, said Jhumku Kohtz, PhD, research professor in the Ken and Ruth Davee Department of Neurology‘s Divison of Comprehensive Neurology and senior author of the study.
“When I began this work, long non-coding RNAs were considered non-functional products of ‘junk’ DNA, or ‘dark matter,’” Kohtz said. “This report is an extension of our work over the last two decades on Evf2, an lncRNA that regulates gene expression and brain development.”
In the current study, scientists analyzed Evf2 during brain development in mouse embryos. Using single-cell transcriptomics, investigators found that Evf2 “guides” an enhancer to chromosomal sites that influence gene expression.
The new details of Evf2 activity reveal a sophisticated system of gene regulation that activates and represses genes, some of which are linked to seizure susceptibility and adult brain function, Kohtz said.
The findings offer new insight into one of biology’s central questions: how genes are selected for expression to create distinct cell types.
“One of the key questions in the field of biology is how genes, arranged on linear chromosomes, are selected for expression,” Kohtz said. “Here, we define roles for Evf2 direct RNA binding, specific RNA binding proteins and DNA sequences in selective gene regulation. A surprising outcome is that Evf2 RNA binding patterns across each chromosome are distinct, revealing a potentially novel chromosome organizing principle.”
This principle may represent a new layer of genomic architecture, Kohtz said. The study also highlights Evf2’s regulation of a network of seizure-related genes in the embryonic brain, which could influence adult circuitry and seizure susceptibility.
Looking ahead, Kohtz and her collaborators plan to continue studying Evf2 and how it contributes to chromosomal organization. The team also hopes to understand how Evf2 functions in human brains, she said.
The study was supported by National Institute of Mental Health grants R01MH111267, R03MH126145 and RF1AG068140.
