Genes Associated with Pancreas Development and Function Maintain Open Chromatin in iPSCs Generated from Human...

Area of Science:

• Stem cell biology
• Endocrinology
• Genomics

Background:

• Current in vitro islet differentiation protocols exhibit heterogeneity and low efficiency.
• Induced pluripotent stem cells (iPSCs) from pancreatic beta cells (BiPSCs) demonstrate preferential differentiation toward endocrine pancreas-like cells compared to fibroblast-derived iPSCs (FiPSCs).

Purpose of the Study:

• To identify genomic differences in chromatin accessibility between BiPSCs and FiPSCs.
• To uncover regulatory elements and genes associated with enhanced islet-lineage commitment in BiPSCs.

Main Methods:

• Genome-wide open chromatin interrogation using ATAC-seq in BiPSCs and FiPSCs.
• Identification and analysis of differential open chromatin sites (DOCS).

Main Results:

• Approximately 8.3k significant DOCS were identified between BiPSCs and FiPSCs.
• BiPSC-specific accessible chromatin regions (Bi-DOCS) were enriched for endodermal development regulators (e.g., FOXA2 binding sites) and genes implicated in monogenic diabetes (e.g., PDX1, NKX2-2, HNF1A).
• Bi-DOCS correlated with increased gene expression in BiPSC-derived definitive endoderm and pancreatic progenitor cells.

Conclusions:

• Differential chromatin accessibility in BiPSCs highlights key genes and pathways governing islet-lineage commitment.
• These findings can advance differentiation protocols, diabetes disease modeling, and therapeutic strategies.