Abstract
SummaryCurrent 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.
Highlights
Human pancreatic islets have been placed center stage in type 2 diabetes pathogenesis (Dimas et al, 2014)
All but two lines (BiPSC-D1 and D2, Table S1) were karyotypically normal; as shown in the section on ‘‘In Silico and Cellular Validation of differential open chromatin sites (DOCS)’’, removing these two lines did not substantially alter the results reported in this study
Consistent with the pluripotent nature of both Induced pluripotent stem cells (iPSCs) subtypes, we found the open chromatin pattern to be highly similar between beta-cell-derived iPSCs (BiPSCs) and FiPSCs, and clearly distinct from primary human islets
Summary
Human pancreatic islets have been placed center stage in type 2 diabetes pathogenesis (Dimas et al, 2014). Current disease-modeling efforts are often frustrated by the limited availability of human physiologically authentic islet-like cells. Derivation of endocrine pancreas from iPSCs represents one solution for generating sufficient numbers of physiologically and disease-relevant human islet-like cells (Nostro et al, 2015; Pagliuca et al, 2014; Rezania et al, 2014). Differentiation efficiency varies across iPSC lines (Bar-Nur et al, 2011; Burrows et al, 2016; Kim et al, 2010; Kyttala et al, 2016; Polo et al, 2010; Rouhani et al, 2014). There is evidence to support an epigenetic ‘‘memory’’ in iPSCs (Bar-Nur et al, 2011; Kim et al, 2010; Polo et al, 2010), this comprising epigenomic and transcriptomic signatures of the original reprogrammed cell type, which may erode over prolonged periods of passaging in culture (BarNur et al, 2011; Kim et al, 2010; Polo et al, 2010)
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