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

Thurner M., Shenhav L., Wesolowska-Andersen A., Bennett AJ., Barrett A., Gloyn AL., McCarthy MI., Beer NL., Efrat S.

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.

DOI

10.1016/j.stemcr.2017.09.020

Type

Journal article

Journal

Stem Cell Reports

Publication Date

14/11/2017

Volume

9

Pages

1395 - 1405

Keywords

beta-cell, diabetes, endoderm differentiation, epigenetics, genomics, human iPS cell, pancreas, Cells, Cultured, Cellular Reprogramming, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 3-beta, Homeodomain Proteins, Humans, Induced Pluripotent Stem Cells, Insulin-Secreting Cells, Protein Binding, Trans-Activators, Transcription Factors, Zebrafish Proteins

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