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

Area of Science:

• Reproductive biology
• Metabolic endocrinology
• Epigenetics

Background:

• Maternal pancreatic beta-cells adapt to pregnancy demands, but maladaptation causes gestational diabetes mellitus.
• Mechanisms of beta-cell adaptation during pregnancy are poorly understood.
• Gestational diabetes mellitus (GDM) poses risks to maternal and fetal health.

Purpose of the Study:

• To elucidate the single-cell mechanisms of beta-cell adaptation during pregnancy.
• To identify key molecular players and epigenetic pathways involved in beta-cell plasticity.
• To explore the role of Acetyl-CoA Synthetase 2 (ACSS2) in pregnancy-induced metabolic stress.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of mouse pancreatic beta-cells.
• Genetic analyses, including beta-cell-specific gene deletion.
• Chromatin immunoprecipitation (ChIP) assays to assess histone acetylation.
• High-fat diet (HFD) and standard diet (SD) feeding studies.

Main Results:

• Identified a precise beta-cell adaptation process involving metabolic stress, increased acetyl-CoA biosynthesis, and histone acetylation.
• STAT3 and ACSS2 promote histone acetylation of pregnancy-associated genes.
• HFD induces chromatin hyperacetylation, leading to beta-cell dysfunction, which is rescued by Acss2 deletion.
• ACSS2 is crucial for early adaptation in HFD-fed mice but not SD-fed mice.

Conclusions:

• Uncovered a detailed, single-cell regulated beta-cell adaptation process during pregnancy.
• Identified a specific epigenetic pathway (STAT3/p300/ACSS2) governing beta-cell plasticity.
• Findings offer insights into GDM pathogenesis and potential therapeutic targets for beta-cell dysfunction.