- Pham, Vanha N;
- Bruemmer, Kevin J;
- Toh, Joel DW;
- Ge, Eva J;
- Tenney, Logan;
- Ward, Carl C;
- Dingler, Felix A;
- Millington, Christopher L;
- Garcia-Prieto, Carlos A;
- Pulos-Holmes, Mia C;
- Ingolia, Nicholas T;
- Pontel, Lucas B;
- Esteller, Manel;
- Patel, Ketan J;
- Nomura, Daniel K;
- Chang, Christopher J
One-carbon metabolism is an essential branch of cellular metabolism that intersects with epigenetic regulation. In this work, we show how formaldehyde (FA), a one-carbon unit derived from both endogenous sources and environmental exposure, regulates one-carbon metabolism by inhibiting the biosynthesis of S-adenosylmethionine (SAM), the major methyl donor in cells. FA reacts with privileged, hyperreactive cysteine sites in the proteome, including Cys120 in S-adenosylmethionine synthase isoform type-1 (MAT1A). FA exposure inhibited MAT1A activity and decreased SAM production with MAT-isoform specificity. A genetic mouse model of chronic FA overload showed a decrease n SAM and in methylation on selected histones and genes. Epigenetic and transcriptional regulation of Mat1a and related genes function as compensatory mechanisms for FA-dependent SAM depletion, revealing a biochemical feedback cycle between FA and SAM one-carbon units.