Methionine metabolism is essential for SIRT1-regulated mouse embryonic stem cell maintenance and embryonic development.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Tang, S; Fang, Y; Huang, G; Xu, X; Padilla-Banks, E; Fan, W; Xu, Q; Sanderson, SM; Foley, JF; Dowdy, S; McBurney, MW; Fargo, DC; Williams, CJ; Locasale, JW; Guan, Z; Li, X

Published Date

  • November 2, 2017

Published In

Volume / Issue

  • 36 / 21

Start / End Page

  • 3175 - 3193

PubMed ID

  • 29021282

Pubmed Central ID

  • 29021282

Electronic International Standard Serial Number (EISSN)

  • 1460-2075

Digital Object Identifier (DOI)

  • 10.15252/embj.201796708

Language

  • eng

Conference Location

  • England