Hidden DNA regulators may drive neurodevelopmental disorders by reducing FOXG1 protein
A new study from the laboratory of Gemma Carvill, Ph.D., associate professor in the Ken and Ruth Davee Department of Neurology's Division of Epilepsy and Clinical Neurophysiology, has uncovered variants in noncoding regulatory regions of the genome that contribute to the development of neurodevelopmental disorders.
A recent study conducted by researchers at the Ken and Ruth Davee Department of Neurology's Division of Epilepsy and Clinical Neurophysiology has identified noncoding regulatory regions of the genome that may contribute to the development of neurodevelopmental disorders. Published in Nature Communications, these findings could pave the way for more targeted precision therapies.
Most neurodevelopmental disorders have a genetic basis, and many individuals with unexplained symptoms may carry noncoding variants that disrupt the function of cis-regulatory elements, which are responsible for regulating gene expression. While patients typically receive symptom management and not a cure, researchers aim to find the genetic cause of these disorders and target the gene itself.
The study focused on the FOXG1 gene, which is known to play a role in neurodevelopmental disorders and can cause a similar clinical phenotype when pathogenic variants are present. Researchers utilized the DECIPHER database to identify 14q12 microdeletions downstream of FOXG1 in individuals with epilepsy and related neurodevelopmental disorders.
By employing CRISPR-Cas9 gene editing, they created these deletions in HAP1 human cell lines expressing FOXG1, leading to a decrease in FOXG1 protein levels, similar to what is observed in patients with coding variants. Additionally, using chromatin conformation capture techniques, the scientists identified cis-regulatory elements in the 14q12 region that promote FOXG1 expression.
These findings suggest that noncoding regions of the genome can drive neurodevelopmental disorders, and the research team plans to investigate the effects of structural variants in other noncoding regions of the genome to develop gene-targeting therapies for patients.
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