Shared and distinct effects of mood stabilizers on epigenetic machinery gene expression: an exploratory study in HeLa...

Mood stabilizers (MS) are the cornerstone of maintenance treatment for bipolar disorder. However, their mechanisms of action remain only partially understood. Increasing evidence suggests that MS may exert part of their therapeutic effects through epigenetic modulations. In this exploratory study, we investigated the effects of therapeutic concentrations of six MS - valproic acid (VPA), lithium, lamotrigine, risperidone, aripiprazole, and quetiapine - on the expression of 82 genes involved in DNA methylations and histone modifications in HeLa cells. After seven days of exposure, VPA induced the most extensive transcriptional changes, with differential expression of 17 out of 82 genes, predominantly involved in histone modifications (acetylation, methylation, phosphorylation, ubiquitination). Notably, VPA upregulated HDAC1, HDAC2, HDAC9, HDAC11, KDM5B, and PAK1 mRNA levels with fold-changes >1.3. Corresponding increased protein levels were observed only for KDM5B and PAK1. VPA also induced direct inhibition of total HDAC activity, unlike lithium and quetiapine. Lithium and quetiapine upregulated HDAC2 and ESCO1 mRNA levels. Lithium and quetiapine did not modify HDAC2 protein levels. Other MS showed no significant transcriptional effects at day 7. Overall, MS-induced transcriptional changes were mainly restricted to genes involved in histone modifications, with minimal effects on DNA methylation-related genes. These findings suggest that MS, particularly VPA, modulate the transcription of epigenetic machinery genes in HeLa cells. HDAC2 upregulation may represent a shared transcriptional response across several MS, although the absence of consistent protein-level changes warrants caution. These results are exploratory and require replication in more physiologically relevant models to determine their biological and clinical significance.