Heterogeneous enhancer states orchestrate β cell responses to metabolic stress

Area of Science:

• Molecular Biology
• Epigenetics
• Diabetes Research

Background:

• Obesity is a major driver of type 2 diabetes, largely due to impaired pancreatic beta-cell function.
• Understanding the epigenetic mechanisms behind beta-cell dysfunction at a single-cell level is crucial but challenging.

Purpose of the Study:

• To investigate the epigenetic landscape, specifically enhancer activity (H3K4me1, H3K27ac), in individual beta cells during obesity-induced dysfunction.
• To identify gene expression patterns and enhancer states associated with the trajectory of beta-cell dysfunction.

Main Methods:

• Single-nuclei RNA sequencing combined with ChIP-sequencing for H3K4me1 and H3K27ac marks in mouse islets.
• Analysis of gene signatures and enhancer states in beta cells from lean and obese mice.
• Cell-cell communication analysis to identify signaling pathways.

Main Results:

• Distinct gene signatures and enhancer states correlate with beta-cell dysfunction.
• Some metabolic stress-induced genes show concordant enhancer changes, while others are regulated by H3K4me1 or H3K27ac dynamics independently.
• A subset of primed enhancers (H3K4me1+H3K27ac-) occupied by FoxA2 in lean beta cells are lost under metabolic stress.
• Nerve growth factor (NGF) identified as a protective paracrine signal that represses endoplasmic reticulum (ER) stress.

Conclusions:

• Heterogeneous enhancer responses to metabolic challenges occur in individual beta cells.
• Epigenetic modifications, including enhancer dynamics, play a significant role in obesity-induced beta-cell dysfunction.
• NGF signaling offers a potential therapeutic target for preserving beta-cell function.