DNA glycosylases Ogg1 and Mutyh mediate gene expression of PRC2 targets important for memory formation (BiSulfite-Seq)
Base excision repair initiated by DNA glycosylases is known to preserve genomic integrity by removing damaged bases. Besides, DNA glycosylases Ogg1 and Mutyh were shown to alter the hippocampal transcriptome associated with cognition but independent of DNA damage repair. However, the underlying molecular mechanisms are not fully understood. 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 but not associative long-term memory. Mechanistically, Ogg1 and Mutyh modulate DNA methylation of polycomb repressive complex 2 (PRC2) target genes. We find that the occupancy of PRC2 and histone modifications associated with PRC2 activity depend on Ogg1 and Mutyh in neurons and glia. These epigenetic changes correlate with cell-type specificdifferences in gene expression of PRC2 targets. Our results uncover 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. Overall design: Transcriptomic and epigenetic analysis of WT and DNA glycosylase deficient (Ogg1-/-, Mutyh-/- and Ogg1xMutyh-/-) C57/BL6N mice in hippocampus. Bisulfite methylation sequencing of whole hippocampus DNA. RNA-sequencing of nuclear RNA from NeuN+ or NeuN- sorted hippocampal nuclei. ChIP-sequencing for PRC2 component Suz12 and two histone methylation markers (H4K4me3 and H3K27me3) from NeuN+ or NeuN- sorted hippocampal nuclei.