CHD3 and CHD4 coordinate gene expression programs to maintain β-cell function and identity in vivo.

Area of Science:

• Endocrinology
• Molecular Biology
• Epigenetics

Background:

• Pancreatic beta cells require precise chromatin regulation for identity and insulin secretion.
• The NuRD complex, including CHD3 and CHD4, plays a role in chromatin remodeling.

Purpose of the Study:

• To investigate the cooperative and compensatory roles of CHD3 and CHD4 in maintaining beta cell function.
• To understand the molecular mechanisms underlying beta cell dysfunction upon loss of CHD3 and CHD4.

Main Methods:

• Beta-cell specific deletion of CHD3 and CHD4 in mouse models.
• Transcriptomic and chromatin accessibility analyses.
• Electrophysiological recordings and analysis of human pseudoislets.

Main Results:

• Combined deletion of CHD3 and CHD4 led to glucose intolerance, impaired insulin secretion, and reduced beta cell area.
• Loss of CHD3/4 downregulated beta cell maturity genes, altered enhancer accessibility, and derepressed alternative cell programs.
• A compensatory increase in CHD3 upon CHD4 loss buffered stress but ultimately failed under chronic metabolic challenge.

Conclusions:

• CHD3 and CHD4 are essential cooperative regulators of beta cell transcriptional programs.
• A transient compensatory mechanism involving CHD3 protects beta cells under stress but is insufficient to prevent diabetes progression.
• These findings link CHD3 and CHD4 to human beta cell function and diabetes.