FBS Colloquia No.341KOKORO-Biology Group

Role of DNA polymerase β-dependent active DNA demethylation in cortical development

Somatic mutations in cortical neurons, arising from DNA damage during development, have been implicated in the pathogenesis of psychiatric disorders. However, the underlying mechanisms remain elusive. Through our research on DNA polymerase β (Polβ), a DNA repair enzyme, during mouse cortical development, we have uncovered its role in active DNA demethylation, an epigenetic regulation process. This process initiates with the activity of TET enzymes, leading to the removal of 5-methylcytosine, followed by Polβ filling the gap with cytosine. Disruption of this process results in mutagenesis and aberrant gene expression, subsequently influencing circuit formation and behavior. In this seminar, I will present the molecular mechanisms underpinning cortical development, characterized by the interplay of epigenome plasticity, genome stability, and somatic mutagenesis.