IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58322-3.html
   My bibliography  Save this article

ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice

Author

Listed:
  • Yu Zhang

    (Peking University
    Peking University
    Peking University)

  • Shuang He

    (Peking University
    Peking University)

  • Xi Wang

    (Peking University
    Peking University)

  • Xin Wang

    (Peking University
    Peking University)

  • Mao-Yang He

    (Peking University
    Peking University
    PKU-Tsinghua-NIBS Graduate Program; Peking University)

  • Xin-Xin Yu

    (Peking University
    Peking University
    Peking University)

  • Cheng-Ran Xu

    (Peking University
    Peking University
    Peking University)

Abstract

Maternal pancreatic β-cells undergo adaptive changes to meet the metabolic demands of pregnancy, and disruptions in this adaptation can lead to gestational diabetes mellitus. However, the mechanisms governing this adaptation remain largely unexplored. Using single-cell transcriptome combined with genetic analyses, we identified a precise process of β-cell adaptation in mice, characterized by progressive metabolic stress-related β-cell dysfunction, increased acetyl-CoA biosynthesis, and gene element-specific histone acetylation. STAT3 recruits p300 to promote histone acetylation of pregnancy-associated genes, a process enhanced by Acetyl-CoA Synthetase 2 (ACSS2). High-fat feeding induces hyperacetylation of chromatin regions specifically opened during pregnancy, leading to the overexpression of genes that impair β-cell function. However, these impairments can be rescued by β-cell-specific deletion of Acss2. Notably, ACSS2 is functionally implicated in the early establishment of β-cell adaptation in HFD-fed mice but does not appear to play a role in standard diet-fed mice until after the initiation of adaptation. Our study uncovers a finely regulated β-cell adaptation process at the single-cell level during pregnancy and identifies a specific epigenetic pathway that governs this process. These findings provide insights into β-cell plasticity and potential therapeutic strategies for gestational diabetes mellitus.

Suggested Citation

  • Yu Zhang & Shuang He & Xi Wang & Xin Wang & Mao-Yang He & Xin-Xin Yu & Cheng-Ran Xu, 2025. "ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58322-3
    DOI: 10.1038/s41467-025-58322-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58322-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-58322-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Philipp Mews & Greg Donahue & Adam M. Drake & Vincent Luczak & Ted Abel & Shelley L. Berger, 2017. "Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory," Nature, Nature, vol. 546(7658), pages 381-386, June.
    2. Jingyi Wu & Jiawei Xu & Bofeng Liu & Guidong Yao & Peizhe Wang & Zili Lin & Bo Huang & Xuepeng Wang & Tong Li & Senlin Shi & Nan Zhang & Fuyu Duan & Jia Ming & Xiangyang Zhang & Wenbin Niu & Wenyan So, 2018. "Publisher Correction: Chromatin analysis in human early development reveals epigenetic transition during ZGA," Nature, Nature, vol. 560(7718), pages 27-27, August.
    3. Jingyi Wu & Jiawei Xu & Bofeng Liu & Guidong Yao & Peizhe Wang & Zili Lin & Bo Huang & Xuepeng Wang & Tong Li & Senlin Shi & Nan Zhang & Fuyu Duan & Jia Ming & Xiangyang Zhang & Wenbin Niu & Wenyan So, 2018. "Chromatin analysis in human early development reveals epigenetic transition during ZGA," Nature, Nature, vol. 557(7704), pages 256-260, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Julien Pontis & Cyril Pulver & Christopher J. Playfoot & Evarist Planet & Delphine Grun & Sandra Offner & Julien Duc & Andrea Manfrin & Matthias P. Lutolf & Didier Trono, 2022. "Primate-specific transposable elements shape transcriptional networks during human development," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Saurabh J. Pradhan & Puli Chandramouli Reddy & Michael Smutny & Ankita Sharma & Keisuke Sako & Meghana S. Oak & Rini Shah & Mrinmoy Pal & Ojas Deshpande & Greg Dsilva & Yin Tang & Rakesh Mishra & Giri, 2021. "Satb2 acts as a gatekeeper for major developmental transitions during early vertebrate embryogenesis," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    3. Denis Torre & Nancy J. Francoeur & Yael Kalma & Ilana Gross Carmel & Betsaida S. Melo & Gintaras Deikus & Kimaada Allette & Ron Flohr & Maya Fridrikh & Konstantinos Vlachos & Kent Madrid & Hardik Shah, 2023. "Isoform-resolved transcriptome of the human preimplantation embryo," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    4. Yinuo Wang & Adel Elsherbiny & Linda Kessler & Julio Cordero & Haojie Shi & Heike Serke & Olga Lityagina & Felix A. Trogisch & Mona Malek Mohammadi & Ibrahim El-Battrawy & Johannes Backs & Thomas Wiel, 2022. "Lamin A/C-dependent chromatin architecture safeguards naïve pluripotency to prevent aberrant cardiovascular cell fate and function," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    5. Charlotte M. François & Thomas Pihl & Marion Dunoyer de Segonzac & Chloé Hérault & Bruno Hudry, 2023. "Metabolic regulation of proteome stability via N-terminal acetylation controls male germline stem cell differentiation and reproduction," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Li Yang & Jianwei You & Xincheng Yang & Ruishu Jiao & Jie Xu & Yue zhang & Wen Mi & Lingzhi Zhu & Youqiong Ye & Ruobing Ren & Delin Min & Meilin Tang & Li Chen & Fuming Li & Pingyu Liu, 2025. "ACSS2 drives senescence-associated secretory phenotype by limiting purine biosynthesis through PAICS acetylation," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    7. Xiaotong Li & Jason Karpac, 2023. "A distinct Acyl-CoA binding protein (ACBP6) shapes tissue plasticity during nutrient adaptation in Drosophila," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Wen-Xiang Liu & Hai-Ning Liu & Zhan-Ping Weng & Qi Geng & Yue Zhang & Ya-Feng Li & Wei Shen & Yang Zhou & Teng Zhang, 2023. "Maternal vitamin B1 is a determinant for the fate of primordial follicle formation in offspring," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58322-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.