Loss of alkyladenine DNA glycosylase alters gene expression in the developing mouse brain and leads to reduced anxiety and improved memory

Abstract

ABSTRACT Neurodevelopment is a tightly coordinated process, during which the genome is exposed to spectra of endogenous agents at different stages of differentiation. Emerging evidence indicates that DNA damage is an important feature of developing brain, tightly linked to gene expression and neuronal activity. Some of the most frequent DNA damage includes changes to DNA bases, which are recognized by DNA glycosylases and repaired through base excision repair (BER) pathway. The only mammalian DNA glycosylase able to remove frequent alkylated DNA based is alkyladenine DNA glycosylase (Aag, aka Mpg). We recently demonstrated that, besides its role in DNA repair, AAG affects expression of neurodevelopmental genes in human cells. Aag was further proposed to act as reader of epigenetic marks, including 5-hydroxymethylcytosine (5hmC), in the mouse brain. Despite the potential Aag involvement in the key brain processes, the impact of Aag loss on developing brain remains unknown. Here, by using Aag knockout ( Aag -/- ) mice, we show that Aag absence leads to reduced DNA break levels, evident in lowered number of γH2AX foci in postnatal day 5 (P5) hippocampi. This is accompanied by changes in 5hmC signal intensity in different hippocampal regions. Transcriptome analysis of hippocampi and prefrontal cortex, at different developmental stages, indicates that lack of Aag alters gene expression, primarily of genes involved in regulation of response to stress. Across all developmental stages tested aldehyde dehydrogenase 2 ( Aldh2 ) emerged as one of the most prominent genes deregulated in Aag-dependent manner. In line with the changes in hippocampal DNA damage levels and the gene expression, adult Aag -/- mice exhibit altered behavior, evident in decreased anxiety levels determined in the Elevated Zero Maze and increased alternations in the Elevated T Maze tests. Taken together these results suggests that Aag has functions in modulation of genome dynamics during brain development, important for animal behavior. Highlights Aag loss results in reduced DNA damage signal in developing hippocampus; 5hmC signal intensity is perturbed in hippocampal regions of Aag -/- mice; Gene expression is altered in Aag -/- hippocampus and prefrontal cortex; Aag represses Aldh2 expression; Aag -/- mice have reduced anxiety and improved memory.