Methionine metabolism is essential for SIRT 1‐regulated mouse embryonic stem cell maintenance and embryonic development

Abstract

Methionine metabolism is critical for epigenetic maintenance, redox homeostasis, and animal development. However, the regula-tion of methionine metabolism remains unclear. Here, we provide evidence that SIRT1, the most conserved mammalian NAD + -depen-dent protein deacetylase, is critically involved in modulating methionine metabolism, thereby impacting maintenance of mouse embryonic stem cells (mESCs) and subsequent embryogenesis. We demonstrate that SIRT1-deficient mESCs are hypersensitive to methionine restriction/depletion-induced differentiation and apop-tosis, primarily due to a reduced conversion of methionine to S-adenosylmethionine. This reduction markedly decreases methy-lation levels of histones, resulting in dramatic alterations in gene expression profiles. Mechanistically, we discover that the enzyme converting methionine to S-adenosylmethionine in mESCs, methionine adenosyltransferase 2a (MAT2a), is under control of Myc and SIRT1. Consistently, SIRT1 KO embryos display reduced Mat2a expression and histone methylation and are sensitive to maternal methionine restriction-induced lethality, whereas mater-nal methionine supplementation increases the survival of SIRT1 KO newborn mice. Our findings uncover a novel regulatory mechanism for methionine metabolism and highlight the importance of methionine metabolism in SIRT1-mediated mESC maintenance and embryonic development.