Gene regulatory proteins TET2 and TP63 affect the expression of the human D-amino acid oxidase gene

Abstract D-amino acid oxidase (DAO) is a key enzyme in D-amino acid metabolism, influencing various physiological and pathological processes, including kidney disease. However, the mechanisms governing DAO gene expression remain largely unknown. In this study, we investigated the transcriptional regulation of the DAO gene by identifying factors affecting DAO expression that bind to its promoter and intron 1 regions and assessing their effects on DAO expression. We also examined the role of DNA methylation in this process. Using ChIP-Atlas and integrative genomics analysis, we identified 20 candidate gene regulatory proteins. Etoposide treatment of HK-2 human renal tubular epithelial cells increased DAO expression, accompanied by significant upregulation of TET2 and TP63 among candidate gene regulatory proteins. Knockdown of TET2 or TP63 using small interfering RNA (siRNA) significantly reduced DAO expression. Bisulfite sequencing of the DAO promoter region revealed no significant correlation between DNA methylation and DAO expression. These findings suggest TET2 and TP63 as novel factors affecting DAO expression, shedding light on the transcriptional control of D-amino acid metabolism. Given the role of D-amino acids in kidney function, inflammation, and cancer, elucidating DAO regulation may facilitate the development of new biomarkers and therapeutic strategies for related diseases.