ACSS2 mediates an epigenetic pathway to regulate maternal Beta-cell adaptation and progression of gestational diabetes (scRNA-Seq)
Maternal pancreatic Beta-cell state is adapted to accommodate gestation metabolism. Defects in this process may cause gestational diabetes mellitus (GDM), with risk factors including a high-calorie diet during pregnancy. However, the regulatory mechanism of maternal Beta-cell adaptation is largely unknown. Using single-cell transcriptome combining genetic analyses, we discovered a precise process of Beta-cell adaptation in mice which is associated with progression of metabolic stress-related Beta-cell dysfunction, increased 40393969acetyl-CoA biosynthesis, and gene element-specific histone acetylation. STAT3 recruits p300 to promote histone acetylation levels of pregnancy-associated genes, and Acetyl-CoA Synthetase 2 (ACSS2) enhances this process. High-fat feeding causes hyperacetylation of chromatin that is specifically opened during pregnancy, which results in overexpression of genes that impair Beta-cell functions and, consequently, hyperglycemia. However, these impairments can be rescued by Beta-cell-specific deletion of Acss2. Therefore, our study reveals a precise adaptation process in Beta-cells at the single-cell level during pregnancy and a specific epigenetic pathway that regulates this process. We also explain the epigenetic regulatory mechanism by which a high-fat diet can lead to GDM and identify ACSS2 as a potential molecular target for controlling the progression of GDM. Overall design: scRNA-seq of mouse pancreatic islets during gestation and puerperium days.