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

## TL;DR

CHD3 and CHD4 work together to maintain pancreatic β-cell function and identity, and their loss leads to impaired insulin secretion and diabetes-like symptoms.

## Contribution

The study reveals cooperative and compensatory roles of CHD3 and CHD4 in β-cell function and identifies a transient resilience mechanism under metabolic stress.

## Key findings

- Combined deletion of CHD3 and CHD4 causes glucose intolerance and impaired insulin secretion.
- Loss of CHD3/CHD4 leads to downregulation of β-cell maturity genes and derepression of alternative islet cell programs.
- CHD3 compensates for CHD4 loss temporarily but fails under chronic metabolic stress.

## Abstract

Pancreatic β cells require tightly regulated chromatin architecture to preserve their identity and sustain glucose-stimulated insulin secretion. Here, we define cooperative and compensatory roles for the NuRD complex remodelers CHD3 and CHD4 in maintaining β-cell function. While β-cell-specific loss of CHD3 alone had little effect, combined deletion of CHD3 and CHD4 caused severe glucose intolerance, impaired insulin secretion, and reduced β-cell area. Transcriptomic and chromatin accessibility analyses revealed downregulation of key β-cell maturity genes, reduced accessibility at β-cell enhancers, and derepression of disallowed, developmental, and alternative islet cell programs, accompanied by altered ion channel expression and defective electrophysiological properties. Mechanistically, CHD3 protein abundance increased upon CHD4 loss and CHD3:PDX1 interactions were dynamically enhanced during early high-fat diet challenge, buffering against β-cell stress before collapsing under chronic conditions. Human pseudoislets recapitulated conserved features of CHD3/4 deficiency, linking these remodelers to human β-cell function. Together, our findings establish CHD3 and CHD4 as cooperative guardians of β-cell transcriptional programs and uncover a compensatory mechanism that transiently preserves β-cell resilience under metabolic stress but fails in diabetes progression.