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.
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 role of SIRT1 in regulation of transcription and splicing in mouse embryonic stem cellsNCBI Gene Expression Omnibus, GSE163920.
- Xiaoling Li
- Zefeng Wang
- Jian Xu
- Xiaojuan Fan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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
- Peter Tontonoz, University of California, Los Angeles, United States
- Received: February 11, 2021
- Accepted: May 26, 2021
- Accepted Manuscript published: May 27, 2021 (version 1)
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.