Methionine metabolism is essential for SIRT1‐regulated mouse embryonic stem cell maintenance and embryonic development. (11th October 2017)

• Record Type: Journal Article
• Authors: Tang, Shuang; Fang, Yi; Huang, Gang; Xu, Xiaojiang; Padilla‐Banks, Elizabeth; Fan, Wei; Xu, Qing; Sanderson, Sydney M; Foley, Julie F; Dowdy, Scotty; McBurney, Michael W; Fargo, David C; Williams, Carmen J; Locasale, Jason W; Guan, Ziqiang; Li, Xiaoling
• Is Part Of: EMBO journal. Volume 36:Number 21(2017)
• Page Start: 3175
• Page End: 3193
• Publication Date: 2017-10-11
• Subjects: embryonic development -- histone methylation -- methionine -- SAM -- SIRT1; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201796708
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: Methionine metabolism is critical for epigenetic maintenance, redox homeostasis, and animal development. However, the regulation of methionine metabolism remains unclear. Here, we provide evidence that SIRT1, the most conserved mammalian NAD + ‐dependent 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 apoptosis, primarily due to a reduced conversion of methionine to S‐adenosylmethionine. This reduction markedly decreases methylation 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 maternal 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. Synopsis: A SIRT1‐Myc axis affects mouse embryogenesis and epigenetic regulation of mESC function by regulating expression of methionine adenosyltransferase 2. SIRT1 deficiency reduces mESC pluripotency. Loss of SIRT1 in mESCs impairs methionine metabolism and histone methylation. SIRT1‐deficient mESCs are sensitive to methionine restriction‐induced differentiation and apoptosis. SIRT1 regulates methionine metabolism in part through Myc. Compromised mESC pluripotency and neonatal mouse lethality in the absence of SIRT1 is partly due to defective methionine metabolism. Abstract : A SIRT1‐Myc axis affects mouse embryogenesis and epigenetic regulation of mESC function by regulating expression of methionine adenosyltransferase 2.