Dynamic 5-hydroxymethylcytosine remodeling associated with synaptic gene programs in the striatum of a Parkinson’s disease mouse model

Abstract

The striatum, a key structure within the basal ganglia, undergoes functional dysregulation following the loss of dopaminergic input, contributing to the motor symptoms of Parkinson’s disease (PD). However, the involvement of DNA hydroxymethylation in striatal dysfunction remains poorly understood. This study aimed to characterize striatal 5-hydroxymethylcytosine (5hmC) profiles and their associations with transcriptional changes across two post-lesion stages in a 6-hydroxydopamine (6-OHDA) mouse model of PD. We profiled the genome-wide 5hmC landscape and transcriptome in the lesioned and contralateral striata of male mice at day 10 and day 30 after unilateral 6-OHDA injection. Global 5hmC levels were lower in the lesioned than in the contralateral striatum at day 10 but higher at day 30. Lesion-associated 5hmC remodeling and transcriptional responses were time-dependent. Functional enrichment linked genes associated with differentially hydroxymethylated regions (DhMRs) to neuronal and synaptic processes, with distinct functional profiles across time points and interaction directions. Integration of the hydroxymethylome and transcriptome suggested different patterns of association between 5hmC remodeling and gene expression in separate analyses at day 10 and day 30, with this correspondence appearing more evident at day 10. At both time points, the gene sets with concordant hydroxymethylation and expression changes were enriched for synapse-related processes, suggesting a shared synaptic functional theme across the hydroxymethylome and transcriptome. Among the TET family members, only TET1 showed temporal changes in abundance that paralleled striatal 5hmC dynamics. Together, these findings demonstrate dynamic remodeling of striatal 5hmC in male mice following 6-OHDA lesioning and identify associations between hydroxymethylation changes and synaptic gene programs, providing insight into the epigenetic features of PD-associated striatal dysfunction.