DNA glycosylases Ogg1 and Mutyh influence gene expression of PRC2 targets associated with cognition

Base excision repair, initiated by DNA glycosylases, preserves genomic integrity by removing damaged bases. DNA glycosylases Ogg1 and Mutyh were shown to alter the hippocampal transcriptome independently of DNA damage repair. However, the role of DNA glycosylases as transcriptional regulators and their involvement in cognition remain unclear. Here, we combine transcriptomic and epigenomic analyses of the hippocampus in mice deficient in DNA glycosylases. We report that the combined deficiency of Ogg1 and Mutyh impairs spatial long-term memory. Mechanistically, Ogg1 and Mutyh modulate DNA methylation of polycomb repressive complex 2 (PRC2) target genes. PRC2 occupancy and associated histone post-translational modifications depend on Ogg1 and Mutyh in neurons and glia. These epigenetic changes correlate with cell-type specific differences in gene expression of PRC2 targets. Finally, human genetic data link DNA glycosylase-regulated genes to cognitive function, highlighting a novel role for Ogg1 and Mutyh in modulating the epigenome to control transcriptional responses relevant for brain-related diseases.