Methionine metabolism is essential for SIRT1‐regulated mouse embryonic stem cell maintenance and embryonic development |
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| Authors: | Gang Huang Xiaojiang Xu Elizabeth Padilla‐Banks Wei Fan Qing Xu Sydney M Sanderson Julie F Foley Scotty Dowdy Michael W McBurney Jason W Locasale Ziqiang Guan Xiaoling Li |
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| Affiliation: | 1. Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;2. Shanghai University of Medicine & Health Sciences, Shanghai, China;3. Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA;4. Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA;5. Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA;6. Department of Pharmacology and Cancer Biology, Duke Cancer Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA;7. Cellular and Molecular Pathology Branch and Comparative Medicine Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA;8. Program for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, ON, Canada;9. Department of Biochemistry, Duke University Medical Center, Durham, NC, USA;10. Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USAThis article has been contributed to by US Government employees and their work is in the public domain in the USA |
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| 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. |
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| Keywords: | embryonic development histone methylation methionine
SAM
SIRT1 |
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