Sarcosine Remodels DNA Methylation-Linked Transcriptional Networks During Epileptogenesis in the Rat Rapid Hippocampal Kindling Model
Year: 2026
Type: article
Abstract: DNA methylation is a key regulator of epileptogenesis. Sarcosine, a glycine transporter 1 (GlyT1) inhibitor and methyl donor, suppresses kindling-induced epileptogenesis and alters hippocampal DNA methylation, but its locus-specific epigenetic effects remain poorly understood. Here, reduced representation bisulfite sequencing (RRBS) was combined with targeted gene expression analysis in the hippocampus of sarcosine-treated kindled rats. RRBS identified 563, 533, and 390 differentially methylated regions (DMRs), corresponding to 521, 499, and 374 DMR-associated genes, in vehicle-kindled versus sham (vKD vs vSH), sarcosine-kindled versus sham (sKD vs vSH), and sarcosine-kindled versus vehicle-kindled (sKD vs vKD) comparisons, respectively. Pathway enrichment analysis identified 217 significantly affected pathways, including glutamatergic signaling, extracellular matrix (ECM) organization, chromatin regulation, axon guidance, and apoptotic processes. Eleven candidate genes involved in epigenetic regulation, excitatory neurotransmission, and ECM remodeling were selected for transcriptional validation. All 11 genes were significantly upregulated in kindled hippocampi, whereas sarcosine normalized expression of eight genes (Hdac9, Fos, Smad7, Unc5a, Grik2, Gpr37l1, Cacna2d2, and Yy1) toward control levels. Collectively, these findings indicate that sarcosine remodels DNA methylation-associated transcriptional networks during epileptogenesis and support GlyT1 inhibition as a potential disease-modifying strategy for epilepsy.
DOI: 10.3390/ijms27177938
Institutions: University of Nebraska Medical Center, Legacy Health
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7211911976