Valine-restricted diet regulates DNA methylation

The abundancy of intracellular amino acid (AA) levels is precisely sensed by complex machineries to regulate various signaling pathways and control cell functions. Insufficient intracellular AAs may block the release of tRNA molecules from the general control non-derepressible 2 (GCN2), and consequently activate GCN2-ATF4 pathways, which is an indirect mechanism for sensing general AAs levels. Additionally, the intracellular levels of some AAs can be sensed by direct binding to specific sensors. Nowadays, the sensors of arginine and leucine levels are most well-characterized, including CASTor1/2, SLC38A9, Sestrin2 and SAR1B, which regulate the mechanistic target of rapamycin complex 1 (mTORC1) pathway, and couple AA availability to cell growth and metabolism. However, it is still unclear whether and how other types of amino acids are directly sensed to regulate cellular functions except tRNA synthetases. Moreover, epigenetics is known to be regulated by the metabolism of amino acids, but it is incompletely understood how AA abundancy regulates the epigenetics, especially DNA methylation. The long-sought sensor of amino acids for epigenetic regulation has thus far been unknown. Here, we present evidence that valine sensor regulated DNA demethylation.