The Role of Tet2-mediated Hydroxymethylation in Poststroke Depression

Poststroke depression (PSD) is a common complication of stroke and has long been a serious threat to human health. PSD greatly affects neurological recovery, quality of life and mortality. Recent studies have shown that 5-hydroxymethylcytosine (5hmC), an important epigenetic modification, is enriched in the brain and associated with many neurological diseases. However, its role in PSD is still unclear. In this study, middle cerebral artery occlusion (MCAO) and spatial restraint stress were used to successfully induce a PSD mouse model and resulted in reduced 5hmC levels, which were caused by Tet2. Furthermore, genome-wide analysis of 5hmC revealed that differentially hydroxymethylated regions (DhMRs) were associated with PSD. DhMRs were enriched among genes involved in the Wnt signaling pathway, neuron development and learning or memory. In particular, DhMRs were strongly enriched in genes with lymphoid enhancer factor 1 (LEF1) binding motifs. Finally, we demonstrated that decreases in TET2 expression in the brain caused PSD by decreasing Wnt/β-catenin/LEF1 pathway signaling to promote inflammatory factor IL-18 expression. In conclusion, our data highlight the potential for 5hmC modification as a therapeutic target for PSD.