DNA hydroxymethylation shifts in the striatum tracked across stages in a Parkinson’s mouse model

Scientists mapping the epigenetic landscape of the striatum in a mouse model of Parkinson’s disease have reported that 5-hydroxymethylcytosine, a DNA modification increasingly linked to neural gene regulation, undergoes strikingly time-dependent remodeling after dopaminergic input is lost. The study, published in Epigenetics & Chromatin, profiled the genome-wide 5hmC landscape and the transcriptome in the lesioned and contralateral striata of male mice at two stages after a unilateral 6-hydroxydopamine injection, day 10 and day 30 after lesioning. The findings are associations drawn from an animal model and do not establish mechanisms in human Parkinson’s disease.

The central observation was a reversal over time. Global 5hmC levels were lower in the lesioned striatum than in the contralateral side at day 10, but higher at day 30. This directional flip indicates that the hydroxymethylome does not respond to dopaminergic denervation with a single static change but with a dynamic trajectory that differs between early and later post-lesion stages. Lesion-associated 5hmC remodeling and the accompanying transcriptional responses were both time-dependent, with distinct functional profiles across the two time points and across directions of interaction.

Functional enrichment analysis connected genes associated with differentially hydroxymethylated regions, or DhMRs, to neuronal and synaptic processes. When the researchers integrated the hydroxymethylome with the transcriptome, they found 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 the earlier time point. At both time points, however, the gene sets showing concordant hydroxymethylation and expression changes were enriched for synapse-related processes, suggesting a shared synaptic functional theme across the two molecular layers.

The striatum is a key structure within the basal ganglia, and the study’s background notes that it undergoes functional dysregulation following the loss of dopaminergic input, contributing to the motor symptoms of Parkinson’s disease. Yet the involvement of DNA hydroxymethylation in striatal dysfunction had remained poorly understood, which motivated the systematic characterization of striatal 5hmC profiles and their associations with transcriptional changes across the two post-lesion stages in the 6-OHDA model.

Only TET1 showed temporal changes in abundance that paralleled the striatal 5hmC dynamics, making it the one family member whose protein levels tracked the rise-and-fall pattern of the modification itself. This parallel does not demonstrate that TET1 drives the remodeling, but it marks TET1 as a candidate regulator warranting further investigation in models of dopaminergic lesion.

The authors conclude that the 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 Parkinson’s disease-associated striatal dysfunction. Because the work was conducted in a lesion model rather than in patients, and because the reported relationships are associations rather than demonstrated causal effects, the results should be read as a map of correlated molecular changes within a defined animal context.

Several limitations frame the interpretation. The study examined male mice at two fixed time points after a unilateral lesion, comparing the lesioned striatum with the contralateral side, so the findings do not speak to sex differences, to longer post-lesion intervals, or to the human condition directly. The concordance between hydroxymethylation and expression changes identifies genes whose regulatory marks and transcript levels moved together, but the direction of any regulatory influence remains an open question. The article was shared early as a peer-reviewed, accepted version of record in progress, subject to further edits.

Within those boundaries, the study adds a temporal dimension to a growing body of work connecting DNA hydroxymethylation to neural function. By showing that the 5hmC landscape of the striatum shifts in opposite directions at early and later stages after dopaminergic loss, and that the genes with matched hydroxymethylation and expression changes converge on synaptic processes at both stages, the research provides a reference point for future studies of epigenetic regulation in Parkinson’s disease models and, ultimately, in the human basal ganglia.

Subject of Research: Dynamic striatal DNA hydroxymethylation remodeling in a mouse model of Parkinson's disease

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

Article References: Cui, L., Zhu, S.-G., Liu, Y.-X., Song, Y.-D., Wang, Z.-W., Hou, X.-G., Zhang, F., Lian, Y.-Z., Zhang, X., & Zhu, J.-H. (2026). Dynamic 5-hydroxymethylcytosine remodeling associated with synaptic gene programs in the striatum of a Parkinson’s disease mouse model. Epigenetics & Chromatin. https://doi.org/10.1186/s13072-026-00698-7

Image Credits: AI Generated

DOI: 10.1186/s13072-026-00698-7

Keywords: 5-hydroxymethylcytosine, DNA hydroxymethylation, striatum, Parkinson's disease, 6-OHDA mouse model, epigenetics, synaptic genes, TET1, transcriptome, basal ganglia, dopaminergic lesion, gene expression