Setd1a Loss-of-function Disrupts Epigenetic Regulation of Ribosomal Genes Via Altered DNA Methylation

Background and Hypothesis SETD1A, a histone methyltransferase, is implicated in schizophrenia through rare loss-of-function mutations. While SETD1A regulates gene expression via histone H3K4 methylation, its influence on broader epigenetic dysregulation remains incompletely understood. We explored the hypothesis that SETD1A haploinsufficiency contributes to neurodevelopmental disruptions associated with schizophrenia risk via alterations in DNA methylation.Study Design We profiled DNA methylation in the frontal cortex of Setd1a+/- mice across prenatal and postnatal development using Illumina Mouse Methylation arrays. Differentially methylated positions and regions were identified, and their functional relevance was examined through gene and biological annotation. We integrated these findings with transcriptomic and proteomics datasets, and assessed mitochondrial complex I activity to explore potential downstream functional effects.Study Results Setd1a haploinsufficiency resulted in widespread hypomethylation of genes related to ribosomal function and RNA processing that persisted across all developmental stages. Setd1a-targeted promoter regions and noncoding small nucleolar RNAs were also enriched for differentially methylated sites. Despite the downregulation of mitochondrial gene expression, the same genes were not differentially methylated, and complex I activity in Setd1a+/- mice did not differ significantly from controls. Genes overlapping hypomethylated regions were enriched for common genetic associations with schizophrenia.Conclusions Our findings suggest that SETD1A haploinsufficiency disrupts the epigenetic regulation of ribosomal pathways. These results provide insight into an alternative mechanism through which genetic variation in SETD1A influences developmental and synaptic plasticity, contributing to schizophrenia pathophysiology.