Circular RNA SCMH1 promotes persistent brain repair via N6-methyladenosine methylation post stroke

Area of Science:

• Molecular Biology
• Neuroscience
• Biochemistry

Background:

• Circular RNAs (circRNAs) offer sustained therapeutic effects from single-dose administration.
• The molecular mechanisms behind circRNA persistence remain unclear.
• Understanding circRNA persistence is key for developing advanced nucleic acid therapeutics.

Purpose of the Study:

• To elucidate the molecular basis of sustained therapeutic effects from single-dose circRNA administration.
• To investigate the self-sustaining loop mechanism of circSCMH1 in brain repair.
• To identify key proteins involved in circSCMH1 persistence and efficacy.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq).
• Development of a modified circSCMH1 variant (ΔcircSCMH1) to distinguish endogenous and exogenous sources.
• Utilized genetic animal models, including Exportin-4-deficient mice.

Main Results:

• Exogenous circSCMH1 establishes a self-sustaining loop, elevating endogenous circSCMH1 levels in the peri-infarct region.
• Microglial FTO demethylase activity and YTHDC1 protein are crucial for circSCMH1 biogenesis and nuclear export.
• Impaired nuclear export of circSCMH1 in Exportin-4-deficient mice abolished sustained brain repair and sensorimotor recovery.

Conclusions:

• A single dose of circSCMH1 promotes brain repair via a self-sustaining loop involving endogenous circRNA biogenesis.
• The findings reveal a novel mechanism for prolonged therapeutic efficacy of circRNA therapeutics.
• This approach holds significant translational potential for stroke treatment, minimizing the need for repeated dosing.