Stein, G.; Aly, J. S.; Manzolillo, A.; Lange, L.; Riege, K.; Hussain, I.; Heller, E. A.; Cubillos, S.; Ernst, T. A.; Huebner, C. A.; Turecki, G.; Hoffmann, S.; Engmann, O.

This study reveals a molecular pathway linking vitamin B12, DNA methylation (DNAme), and stress resilience. Chronic stress significantly contributes to mood- and anxiety disorders. Previous and current data suggest a rapid effect of vitamin B12 supplementation on stress resilience. However, the underlying mechanisms are still poorly understood. Through next-generation RNA sequencing, we identified Transthyretin (Ttr) as a key target of vitamin B12, particularly within the prefrontal cortex of male mice. Furthermore, TTR expression was increased postmortem in the prefrontal cortex of male, but not female, depressed patients. Viral-mediated gene transfer demonstrated a causal role of Ttr in behavior and dendritic spine morphology. In stressed mice, vitamin B12 reduced DNAme in the Ttr promoter region. By using in vivo epigenome editing to alter DNAme in the brains of living mice for the first time, we establish a direct causal link between DNAme on Ttr and stress-associated behaviors.