SMUG1 DNA glycosylase modulates reward behaviour through regulation of olfactory receptor gene expression

The SMUG1 DNA glycosylase is the primary enzyme responsible for excising 5-hydroxymethyluracil (5hmU) from genomic DNA. SMUG1 activity is high in the brain, suggesting its crucial role in controlling 5hmU levels in this organ. 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. Chromatin immunoprecipitation revealed that SMUG1 is recruited to AT-rich promoters of olfactory receptor genes, where it regulates 5hmU levels. The persistence of 5hmU in the olfactory receptor promoters leads to deficits in sensory perception of smell and influences reward-related behaviour. Thus, we identify a specific function for SMUG1 in promoting transcription of olfactory receptor genes.