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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Multiple sclerosis (MS) is a fatal neurodegenerative disease characterized by myelin sheath erosion and neuronal death.
• Current MS research focuses on dysregulated genes involved in DNA methylation, a critical process for gene expression and cellular health.
• Serine hydroxymethyltransferase 1 (SHMT1) is upregulated in MS patients and plays a key role in DNA methylation.

Purpose of the Study:

• To characterize DNA secondary structures in the SHMT1 gene.
• To investigate the regulatory role of these structures on SHMT1 expression.
• To explore potential therapeutic targets for multiple sclerosis.

Main Methods:

• Structural analysis of G-quadruplex (GQ) and i-motif (iM) structures in the SHMT1 5' untranslated region (UTR) DNA and mRNA.
• Reporter gene assays to assess the impact of GQ/iM structures on gene and protein expression.

Main Results:

• Hybrid 3 + 1 GQ and iM structures were identified in the SHMT1 DNA 5' UTR.
• A parallel GQ structure was found in the SHMT1 mRNA.
• These GQ/iM structures were shown to suppress reporter gene mRNA levels and protein expression.

Conclusions:

• GQ and iM structures are integral to the regulation of SHMT1.
• These DNA and mRNA secondary structures represent potential therapeutic targets for multiple sclerosis intervention.
• Targeting SHMT1 regulation via GQ/iM structures may offer a novel treatment strategy for MS.