ATP-Citrate Lyase-Dependent Epigenetic Control of Renal Collecting Duct Morphogenesis

Background: Abnormal development of the renal collecting system underlies CAKUT, a major cause of pediatric end-stage renal disease. ATP-citrate lyase (ACLY), an enzyme transporting acetyl-CoA from mitochondria to the nucleus, regulates histone acetylation. Given its abundant expression in collecting duct cells, we investigated ACLY's role in renal collecting duct morphogenesis. Methods: Using Acly knockout mice, we combined single-cell transcriptomics and CUT&Tag-seq to analyze gene expression and histone acetylation in collecting duct cells. Results: Six-week-old Acly knockout mice showed reduced kidney weight, nephron loss, and altered expression of aquaporin-2 and ion channels. Single-cell analysis revealed downregulation of ribosomal protein genes in mutant collecting duct cells. CUT&Tag-seq indicated decreased histone acetylation at ribosomal gene promoters, linking ACLY loss to epigenetic dysregulation. Conclusion: ACLY-driven acetyl-CoA transport may support histone acetylation and ribosomal gene expression critical for collecting duct development. Its impairment may lead to ribosomal dysfunction with compromised ion channel synthesis and metabolic regulation, suggesting a potential mechanism underlying CAKUT. Funding: Government Support – Non-U.S.The mutants show renal malformation.Single-cell analysis revealed downregulation of ribosomal protein genes in Acly mutant cells.