Smug1 DNA glycosylase modulates the perception of smell in mouse brain through downregulation of olfactory receptor genes

The SMUG1-DNA glycosylase is the primary enzyme responsible for excising 5-hydroxymethyluracil (5hmU) from genomic DNA. SMUG1 activity is high in the brain and is therefore proposed to be particularly important for regulating 5hmU levels in the brain. 5hmU has been proposed as an epigenetic mark, but it is still unclear whether, and in which contexts, it may have regulatory functions. Here we show that accumulation of 5hmU in Smug1 deficient mice leads to widespread gene expression alterations across multiple brain regions, and that this is accompanied by a complex behavioural phenotype. We demonstrate that 5hmU serves as a transcriptional regulator of olfactory receptor genes in the olfactory bulb. The persistence of 5hmU in the genome leads to deficits in sensory perception of smell and influences reward-related behaviour. Mechanistically, we identify a specific function for SMUG1 in removing 5hmU from promoters of olfactory receptor genes, promoting transcription and proper olfaction function.