Abstract
Metabolic switch is critical for cell fate determination through metabolic functions, epigenetic modifications, and gene expression. However, the mechanisms underlying these alterations and their functional roles remain unclear. Here, we show that Plin2-mediated moderate lipid hydrolysis is critical for pluripotency of embryonic stem cells (ESCs). Upon exit from pluripotency, lipid droplet (LD)-associated protein Plin2 is recognized by Hsc70 and degraded via chaperone-mediated autophagy to facilitate LD mobilization. Enhancing lipid hydrolysis by Plin2 knockout promotes pluripotency exit, which is recovered by ATGL inhibition. Mechanistically, excessive lipid hydrolysis induces a dramatic lipidomic remodeling characterized by decreased cardiolipin and phosphatidylethanolamine, which triggers defects in mitochondrial cristae and fatty acid oxidation, resulting in reduced acetyl-CoA and histone acetylation. Our results reveal how LD mobilization is regulated and its critical role in ESC pluripotency, and indicate the mechanism linking LD homeostasis to mitochondrial remodeling and epigenetic regulation, which might shed light on development and diseases.
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Data availability
All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary information. Additional data related to this paper may be requested from the authors. ChIP-seq data have been deposited in the Genome Sequence Archive under accession numbers CRA002919 that are publicly accessible at https://bigd.big.ac.cn/gsa.
Code availability
All code needed to evaluate the conclusions in the paper may be requested from the authors.
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Acknowledgements
We thank all members in the lab of Dr Xingguo Liu for helpful suggestions. We also thank Shanghai ProfLeader Biotech Co., Ltd. for the assistance with isotope analysis.
Funding
This work was financially supported by the National Key Research and Development Program of China (2018YFA0107100), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030505), the National Natural Science Foundation projects of China (92157202, 32025010, 98154001, 31900614, 31970709, 81901275, 32070729, 32100619, 32170747), the National Key Research and Development Program of China (2019YFA0904500, 2017YFA0106300, 2017YFA0102900), the Key Research Program, CAS (ZDBS-ZRKJZ-TLC003, QYZDB-SSW-SMC001), and International Cooperation Program, CAS (154144KYSB20200006), Guangdong Province Science and Technology Program (2020B1212060052, 2018GZR110103002, 2020A1515011200, 2020A1515010919, 2020A1515011410, 2021A1515012513, 2021B1515020096, 2022A1515012616), Guangzhou Science and Technology Program (202002030277, 202102020827, 202102080066), and CAS Youth Innovation Promotion Association (to YW and KC).
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Conceptualization: XL, YW, and KC; methodology: XL, YW, KC, and LL; investigation: YW, KC, LL, ZH, YL, GX, HY, HL, ZL, JL, CZ, JZ, DZ, and JW; formal analysis: YW, KC, LL, TW, JN, DY, GP, and WC; writing—original draft: XL and YW; writing—review and editing: XL, YW, and KC; funding acquisition: XL, YW, and KC; supervision: XL.
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All the cells were obtained with approval from the ethics committee of the Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences (GIBH). All the animals were handled according to approved Institutional Animal Care and Use Committee protocols of GIBH.
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Wu, Y., Chen, K., Li, L. et al. Plin2-mediated lipid droplet mobilization accelerates exit from pluripotency by lipidomic remodeling and histone acetylation. Cell Death Differ 29, 2316–2331 (2022). https://doi.org/10.1038/s41418-022-01018-8
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DOI: https://doi.org/10.1038/s41418-022-01018-8
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