BAF60A governs beta cell identity to control systemic glucose homeostasis

Chromatin remodelling is critical for maintaining pancreatic beta cell identity and function, yet the key regulatory mechanisms remain incompletely defined. This study aimed to investigate the role of the switch/sucrose non-fermentable (SWI/SNF) complex subunit BAF60A in preserving beta cell fate and glucose homeostasis.

Pdx1-Cre-mediated BAF60A-knockout (BaBKO) and BAF60A-overexpressing (BaBOE) mice, together with tamoxifen-inducible adult beta cell-specific Smarcd1 knockout (BaBKO^TM) and Isl1 knockout (Isl1BKO^TM) mice, were generated to evaluate the role of BAF60A in vivo. Glucose homeostasis was assessed through glucose tolerance tests, insulin tolerance tests and glucose-stimulated insulin secretion (GSIS) assays. Multiomic analyses, including RNA-seq, ATAC-seq, Cleavage Under Targets and Tagmentation (CUT&Tag) and single-cell RNA-seq, were performed to characterise chromatin accessibility and transcriptional changes. BAF60A-interacting proteins were identified with biotin identification (BioID) and GST pull-down assays. Beta cell lineage tracing was used to assess changes in cell identity. In addition, BAF60A and the dedifferentiation marker ALDH1A3 were examined in pancreatic islets from individuals with and without type 2 diabetes.

BaBKO mice exhibited significant glucose intolerance, impaired GSIS and pronounced loss of beta cell identity, accompanied by the acquisition of non-beta endocrine features. Inducible deletion of Smarcd1 in adult beta cells similarly impaired beta cell maturation and promoted dedifferentiation, as confirmed by lineage tracing. BAF60A deficiency reduced enhancer accessibility and downregulated beta cell identity genes. Mechanistically, BAF60A physically interacts with the transcription factor islet-1 (ISL1) to regulate transcription of target genes. Adult beta cell-specific Isl1 deletion recapitulated key features of BAF60A deficiency and abolished the beneficial effect of BAF60A overexpression on insulin secretion. Conversely, BaBOE mice exhibited improved glucose tolerance and enhanced GSIS under high-fat diet conditions. Adeno-associated virus-mediated BAF60A overexpression markedly reduced beta cell dedifferentiation in BKS-db/db mice. In human type 2 diabetes islets, BAF60A expression was significantly reduced and inversely correlated with ALDH1A3.

This work establishes BAF60A-ISL1-dependent chromatin remodelling as a key mechanism that preserves beta cell identity and function under metabolic stress, providing mechanistic insight into beta cell failure in type 2 diabetes.