N(6)-Methyladenosine Methylomic Landscape of Ureteral Deficiency in Reflux Uropathy and Obstructive Uropathy

BACKGROUND: Congenital anomalies of the kidneys and urinary tracts (CAKUT) represent the most prevalent cause for renal failure in children. The RNA epigenetic modification N(6)-methyladenosine (m(6)A) methylation modulates gene expression and function post-transcriptionally, which has recently been revealed to be critical in organ development. However, it is uncertain whether m(6)A methylation plays a role in the pathogenesis of CAKUT. Thus, we aimed to explore the pattern of m(6)A methylation in CAKUT. METHODS: Using m(6)A-mRNA epitranscriptomic microarray, we investigated the m(6)A methylomic landscape in the ureter tissue of children with obstructive megaureter (M group) and primary vesicoureteral reflux (V group). RESULTS: A total of 228 mRNAs engaged in multiple function-relevant signaling pathways were substantially differential methylated between the “V” and “M” groups. Additionally, 215 RNA-binding proteins that recognize differentially methylated regions were predicted based on public databases. The M group showed significantly higher mRNA levels of m(6)A readers/writers (YTHDF1, YTHDF2, YTHDC1, YTHDC2 and WTAP) and significantly lower mRNA levels of m(6)A eraser (FTO) according to real-time PCR. To further investigate the differentially methylated genes, m(6)A methylome and transcriptome data were integrated to identified 298 hypermethylated mRNAs with differential expressions (265 upregulation and 33 downregulation) and 489 hypomethylated mRNAs with differential expressions (431 upregulation and 58 downregulation) in the M/V comparison. CONCLUSION: The current results highlight the pathogenesis of m(6)A methylation in obstructive and reflux uropathy.