Loss of Epitranscriptomic Modification N6-Methyladenosine (m6A) Reader YTHDF1 Exacerbates Ischemic Brain Injury in a Sexually Dimorphic Manner.

Abstract

N⁶-Methyladenosine (m⁶A) is a neuronal-enriched, reversible post-transcriptional modification that regulates RNA metabolism. The m⁶A-modified RNAs recruit various m⁶A-binding proteins that act as readers. Differential m⁶A methylation patterns are implicated in ischemic brain damage, yet the precise role of m⁶A readers in propagating post-stroke m⁶A signaling remains unclear. We presently evaluated the functional significance of the brain-enriched m⁶A reader YTHDF1, in post-stroke pathophysiology. Focal cerebral ischemia significantly increased YTHDF1 mRNA and protein expression in adult mice of both sexes. YTHDF1^-/- male, but not female, mice subjected to transient middle cerebral artery occlusion (MCAO) showed worsened motor function recovery and increased infarction compared to sex-matched YTHDF1^+/+ mice. YTHDF1^-/- male, but not female, mice subjected to transient MCAO also showed significantly perturbed expression of genes related to inflammation, and increased infiltration of peripheral immune cells into the peri-infarct cortex, compared with sex-matched YTHDF1^+/+ mice. Thus, this study demonstrates a sexual dimorphism of YTHDF1 in regulating post-ischemic inflammation and pathophysiology. Hence, post-stroke epitranscriptomic regulation might be sex-dependent.