ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice
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 combine...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58322-3 |
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| author | Yu Zhang Shuang He Xi Wang Xin Wang Mao-Yang He Xin-Xin Yu Cheng-Ran Xu |
| author_facet | Yu Zhang Shuang He Xi Wang Xin Wang Mao-Yang He Xin-Xin Yu Cheng-Ran Xu |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2ca196730eaa4e13b1ca0252cd6541bf |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2ca196730eaa4e13b1ca0252cd6541bf2025-08-20T03:48:18ZengNature PortfolioNature Communications2041-17232025-05-0116112010.1038/s41467-025-58322-3ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in miceYu Zhang0Shuang He1Xi Wang2Xin Wang3Mao-Yang He4Xin-Xin Yu5Cheng-Ran Xu6State Key Laboratory of Female Fertility Promotion, Department of Medical Genetics, School of Basic Medical Sciences, Peking UniversityPeking-Tsinghua Center for Life Sciences, Peking UniversityPeking-Tsinghua Center for Life Sciences, Peking UniversityPeking-Tsinghua Center for Life Sciences, Peking UniversityAcademy for Advanced Interdisciplinary Studies, Peking UniversityState Key Laboratory of Female Fertility Promotion, Department of Medical Genetics, School of Basic Medical Sciences, Peking UniversityState Key Laboratory of Female Fertility Promotion, Department of Medical Genetics, School of Basic Medical Sciences, Peking UniversityAbstract 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.https://doi.org/10.1038/s41467-025-58322-3 |
| spellingShingle | Yu Zhang Shuang He Xi Wang Xin Wang Mao-Yang He Xin-Xin Yu Cheng-Ran Xu ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice Nature Communications |
| title | ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice |
| title_full | ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice |
| title_fullStr | ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice |
| title_full_unstemmed | ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice |
| title_short | ACSS2 mediates an epigenetic pathway to regulate β-cell adaptation during gestation in mice |
| title_sort | acss2 mediates an epigenetic pathway to regulate β cell adaptation during gestation in mice |
| url | https://doi.org/10.1038/s41467-025-58322-3 |
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