DNA glycosylases Ogg1 and Mutyh mediate gene expression of PRC2 target genes important for neuronal processes underlying memory formation

Abstract

Base excision repair (BER) initiated by DNA glycosylases is known to preserve genomic integrity by removing damaged bases. Recently, several DNA glycosylases were identified as potential readers of epigenetic modifications and proteins involved in BER have been associated with active DNA demethylation. DNA glycosylases Ogg1 and Mutyh were shown to alter the hippocampal transcriptome associated with cognitive function and independent of global DNA damage accumulation. However, the mechanism of DNA glycosylases in regulating cognition and their role in epigenetic remodeling in the brain remains elusive. Here we report that the combined deficiency of Ogg1 and Mutyh impairs spatial but not associative long-term memory. We demonstrate that Ogg1 or Mutyh modulate DNA methylation at gene regulatory regions of polycomb repressive complex 2 (PRC2) target genes in the adult hippocampus. Moreover, we find that the distribution of the PRC2 complex and histone modifications associated with PRC2 activity changes in both hippocampal neurons and glia depend on Ogg1 and Mutyh. Epigenetic alterations correlated with cell-type specific gene expression changes which were associated with pathways important for neuronal function and cognition. Our results provide a novel role for Ogg1 and Mutyh beyond DNA repair in modulating the epigenome to control transcriptional responses in the brain important for memory formation.