TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation

Existing knowledge of the role of epigenetic modifiers in pancreas development has exponentially increased. However, the function of TET dioxygenases in pancreatic endocrine specification remains obscure. We set out to tackle this issue using a human embryonic stem cell (hESC) differentiation system, in which TET1/TET2/TET3 triple knock-out cells displayed severe defects in pancreatic β-cell specification. Integrative whole-genome analysis identified unique cell-type-specific hypermethylated regions (hyper-DMRs) displaying reduced chromatin activity and remarkable enrichment for the binding of FOXA2, a pioneer transcription factor essential for pancreatic endoderm specification. Intriguingly, hundreds of hyper-DMRs recently identified in type-2 diabetes pathogenesis overlapped with the hyper-DMRs we found in TET-deficient cells. Furthermore, transduction of TET1 in TET-deficient cells effectively rescued β-cell differentiation and reversed hypermethylation and suppression of the β-cell determinant PAX4. Genome-wide mapping of TET1 showed that TET1 co-localized at a subset of FOXA2 targets featuring high levels of active chromatin modifications in pancreatic progenitors. Taking these findings together with the defective generation of functional β-cells upon TET1-inactivation, our study not only unveils an essential role of TET1-dependent epigenetic regulation in establishing β-cell identity but also provides a new mechanistic clue regarding the complex crosstalk between TET dioxygenases and pioneer transcription factors in lineage specification.