Work

Gestational low carbamoyl phosphate suppresses TET2-mediated DNA demethylation and induces congenital heart disease in offspring

Year: 2026

Type: article

Abstract: • Maternal low carbamyl phosphate (CP) raises offspring congenital heart disease risk. • Two pregnancy mice models show low CP drives congenital heart disease risk • Low CP reduces TET2 K1339/K1509 carbamylation and impairs its DNA demethylation. • Low CP reduces embryonic hearts 5hmC and inhibits Gata4/Nkx2-5/Notch1 expression. • NCG activation of CPS1 lowers CHD in Cps1 +/- mice and provides translational leverage. Congenital heart disease (CHD) is the most common birth defect worldwide, with over half of cases lacking a defined etiology. Maternal metabolic dysregulation has been implicated in CHD risk, but the specific metabolites and mechanisms involved in embryonic heart development remain poorly understood. Carbamoyl phosphate (CP), a key urea cycle intermediate, has not previously been linked to cardiac morphogenesis. This study aimed to identify maternal metabolites associated with offspring CHD risk and to elucidate the role of CP in regulating cardiac development. Untargeted metabolomic profiling was performed on early-pregnancy serum from 98 mothers of CHD offspring and 50 age-matched controls. Functional validation was performed using two pregnant mouse models: pharmacological inhibition of glutamine metabolism via BPTES and Cps1 heterozygous knockout ( Cps1 +/- ). Rescue experiments were performed with the CPS1 activator N-carbamylglutamate (NCG). Epigenetic mechanisms were investigated by assessing TET2 carbamylation, DNA hydroxymethylation, and cardiogenic gene expression in embryonic hearts. Maternal serum CP levels were significantly reduced in CHD cases and negatively correlated with upstream nutrient levels. In mice, both BPTES treatment and maternal Cps1 knockdown increased CHD incidence in offspring. Conversely, NCG supplementation reduced CHD risk in Cps1 +/– pregnant mouse. Mechanistically, CP depletion impaired TET2 lysine carbamylation at residues K1339 and K1509, decreasing its DNA demethylation activity without affecting protein expression. This resulted in reduced global 5hmC levels and aberrant expression of cardiogenic genes in embryonic hearts. Maternal CP deficiency increases offspring CHD risk by disrupting TET2-mediated DNA demethylation through impaired lysine carbamylation. These findings highlight maternal CP and TET2 carbamylation as potential metabolic-epigenetic targets for CHD prevention.

Source: Journal of Advanced Research

DOI: 10.1016/j.jare.2026.02.021