Genes Associated with Pancreas Development and Function Maintain Open Chromatin in iPSCs Generated from Human Pancreatic Beta Cells

Matthias Thurner, Liraz Shenhav, Agata Wesolowska-Andersen, Amanda J. Bennett, Amy Barrett, Anna L. Gloyn, Mark I. McCarthy, Nicola L. Beer, and Shimon Efrat.
Stem Cell Reports. 2017-11-14;9(5):1395-1405.
Current in vitro islet differentiation protocols suffer from heterogeneity and low efficiency. Induced pluripotent stem cells (iPSCs) derived from pancreatic beta cells (BiPSCs) preferentially differentiate toward endocrine pancreas-like cells versus those from fibroblasts (FiPSCs). We interrogated genome-wide open chromatin in BiPSCs and FiPSCs via ATAC-seq and identified ∼8.3k significant, differential open chromatin sites (DOCS) between the two iPSC subtypes (false discovery rate [FDR] < 0.05). DOCS where chromatin was more accessible in BiPSCs (Bi-DOCS) were significantly enriched for known regulators of endodermal development, including bivalent and weak enhancers, and FOXA2 binding sites (FDR < 0.05). Bi-DOCS were associated with genes related to pancreas development and beta-cell function, including transcription factors mutated in monogenic diabetes (PDX1, NKX2-2, HNF1A; FDR < 0.05). Moreover, Bi-DOCS correlated with enhanced gene expression in BiPSC-derived definitive endoderm and pancreatic progenitor cells. Bi-DOCS therefore highlight genes and pathways governing islet-lineage commitment, which can be exploited for differentiation protocol optimization, diabetes disease modeling, and therapeutic purposes.
Consortium data used in this publication
EGAS00001002591(EGAD00001003780), EGAS00001002591(EGAD00001003759), PRJEB21856