G‑Quadruplex and i‑Motif Structures in the SHMT1 5'UTR Modulate Gene Expression.

Multiple sclerosis is a fatal neurodegenerative disease that progresses by eroding the myelin sheath and exposing the neuron, leading to neuronal degradation and death. While multiple sclerosis remains without an effective treatment or cure, studies have identified genes that are dysregulated in multiple sclerosis patients and predicted to be involved with disease progression. These genes are primarily involved in controlling DNA methylation, a process required for regulating gene expression that is critical for cellular health. Having identified potential genetic risk factors, current research focuses on how to manipulate the expression of these genes, offsetting DNA methylation errors in patients by targeting DNA secondary structure formation. Serine hydroxymethyltransferase 1 (SHMT1) is a key player in DNA methylation and was determined to be upregulated in multiple sclerosis patients. Here, we characterized hybrid 3 + 1 G-quadruplex (GQ) and i-motif (iM) structures in the SHMT1 DNA 5' untranslated region and a parallel GQ in the corresponding mRNA. Additionally, we found that the GQ/iM structures suppress the mRNA levels and protein expression of a reporter gene. Together, these data suggest that GQ/iM structures are necessary for SHMT1 regulation, which could serve as a target for therapeutic intervention for multiple sclerosis patients.