1. Cell Biology
  2. Stem Cells and Regenerative Medicine
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SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc- SMPDL3B

  1. Wei Fan
  2. Shuang Tang
  3. Xiaojuan Fan
  4. Yi Fang
  5. Xiaojiang Xu
  6. Leping Li
  7. Jian Xu
  8. Jian-Liang Li
  9. Zefeng Wang  Is a corresponding author
  10. Xiaoling Li  Is a corresponding author
  1. National Institute of Environmental Health Sciences, United States
  2. Cancer Institute, Fudan University Shanghai Cancer Center, China
  3. CAS-MPG partner institute for computational biology, China
  4. NIEHS, NIH, United States
  5. University of Texas Southwestern Medical Center, United States
Research Article
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Cite this article as: eLife 2021;10:e67452 doi: 10.7554/eLife.67452

Abstract

Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription of Smpdl3b through c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiation in vitro and in vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.

Data availability

The RNA-seq (RNA-seq) data has been deposited to Gene Expression Omnibus under the accession number GSE163920 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE163920). Additional information on DEGs is available from Supplementary File 3. Metabolomics data (lipid alterations) between WT and SIRT1 KO mESCs is available in Supplementary File 1. Sphingolipid profiles between WT and SIRT1 KO mESCs and hESCs are available in Supplementary File 2. All oligos used in the study are available in Supplementary File 4. All antibodies used in the study are available in the Key Resources Table.

The following data sets were generated

Article and author information

Author details

  1. Wei Fan

    Signal Transduction Laboratory, National Institute of Environmental Health Sciences, RTP, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shuang Tang

    Department of Nuclear Medicine, Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiaojuan Fan

    RNA system biology, CAS-MPG partner institute for computational biology, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yi Fang

    Signal Transduction Laboratory, National Institute of Environmental Health Sciences, RTP, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xiaojiang Xu

    Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, RTP, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Leping Li

    Biostatistics and Computational Biology Laboratory, NIEHS, NIH, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jian Xu

    Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1988-7337
  8. Jian-Liang Li

    Integrative Bioinformatics, National Institute of Environmental Health Sciences, Burham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6487-081X
  9. Zefeng Wang

    RNA system biology, CAS-MPG partner institute for computational biology, Shanghai, China
    For correspondence
    wangzefeng@picb.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
  10. Xiaoling Li

    Signal Transduction Laboratory, National Institute of Environmental Health Sciences, RTP, United States
    For correspondence
    lix3@niehs.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5920-7784

Funding

National Institute of Environmental Health Sciences (Z01 ES102205)

  • Xiaoling Li

National Natural Science Foundation of China (31730110 and 31661143031)

  • Zefeng Wang

National Institutes of Health (R01CA230631 and R01DK111430)

  • Jian Xu

China Postdoctoral Science Foundation (2020M681437)

  • Xiaojuan Fan

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were reviewed and approved by National Institute of Environmental Health Sciences Animal Care and Use Committee. All animals were housed, cared for, and used in compliance with the Guide for the Care and Use of Laboratory Animals and housed and used in an Association for the Assessment and Accreditation of Laboratory Animal Care, International (AAALAC) Program.Animal Study Proposal number 2017-0008 STL

Reviewing Editor

  1. Peter Tontonoz, University of California, Los Angeles, United States

Publication history

  1. Received: February 11, 2021
  2. Accepted: May 26, 2021
  3. Accepted Manuscript published: May 27, 2021 (version 1)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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