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 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 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.

Energy Metabolism Regulates Stem Cell Pluripotency

“…In humans, TDH is only expressed as a non-functional pseudogene, thus hESCs rely on methionine metabolism in the same way that mESCs rely on threonine to maintain a high ratio of SAM/SAH (Shiraki et al, 2014). Interestingly, a recent study has also implicated methionine in mESC maintenance downstream of SIRT1 expression (Tang et al, 2017). SIRT1 KO mESCs display an elevated ratio of methionine/SAM due to a reduction in the expression of methionine adenosyltransferase 2a (MAT2a), which catalyzes the conversion of methionine to SAM (Tang et al, 2017).…”

“…Interestingly, a recent study has also implicated methionine in mESC maintenance downstream of SIRT1 expression (Tang et al, 2017). SIRT1 KO mESCs display an elevated ratio of methionine/SAM due to a reduction in the expression of methionine adenosyltransferase 2a (MAT2a), which catalyzes the conversion of methionine to SAM (Tang et al, 2017). Regulation of methionine metabolism appears to be in part through a SIRT1-dependent protein expression of c-MYC and n-MYC, which bind to the MAT2a promoter and induce its expression.…”

Antigen receptor control of methionine metabolism in T cells

“…The dynamic changes in mRNA translation observed by Araki et al (Araki et al 2017) could thus reflect changes in the methionine transport capacity of naïve versus effector versus memory T cells. In this respect the importance of methionine bio-availability to other cell lineages is now recognized eg for liver cells and embryonic stem cells (Tang et al 2017;Shiraki et al 2014;Mentch et al 2015). However, these studies do not explore or discuss the possibility that methionine availability to cells is determined by regulated expression of methionine transporters.…”

Demethylation of the Protein Phosphatase PP2A Promotes Demethylation of Histones to Enable Their Function as a Methyl Group Sink

“…Just as intracellular SAM amounts can influence histone methylation rates (Dobosy et al, 2008;Mentch et al, 2015;Shiraki et al, 2014;Tang et al, 2017;Ye et al, 2017), amounts of cofactors required for the removal of these marks can influence rates of demethylation. In particular, cellular levels of a-ketoglutarate (a-KG) promote oxidative demethylation of methylatedlysine residues within histones and 5-methylcytosine (5mC) bases within DNA (Carey et al, 2015;Kohli and Zhang, 2013;Xiao et al, 2012), which is required for the maintenance of pluripotency (Carey et al, 2015).…”