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

N-Methyladenosine (mA) is a neuronal-enriched, reversible post-transcriptional modification that regulates RNA metabolism. The mA-modified RNAs recruit various mA-binding proteins that act as readers. Differential mA methylation patterns are implicated in ischemic brain damage, yet the precise role of mA readers in propagating post-stroke mA signaling remains unclear. We presently evaluated the functional significance of the brain-enriched mA 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.