Sonic hedgehog signals hinder the transcriptional network necessary for pancreatic endoderm formation from human embryonic stem cells

Hedgehog morphogens govern multiple aspects of pancreas organogenesis and functioning with diverse outcomes across species. Although most current differentiation protocols repress Sonic hedgehog (SHH) signals during in vitro endocrine specification, the role mechanisms through which SHH pathway antagonizes development human embryonic stem (hES) cell remain unclear. We modulated signaling at transitory stages hES cell-derived pancreatic progenitors analyzed effect on cellular fate decisions. identify as a negative regulator endoderm formation up-regulation set pancreatobiliary markers required for ductal including SOX17, FOXA2, HNF1β, HNF6, PDX1, SOX9. Surprisingly, active impeded group epithelium markers, HNF4α, HHEX, PAX6, PTF1α. To understand how transcription these specific we Polycomb proteins. found differential expression Repressive Complex 1 subunit, BMI1 upon Shh modulation progenitors. Ectopic activation results over-expression its associated repressive histone mark, H2AK119Ub1, multipotent Our data suggest that restricts program by limiting progenitor cells acquiring epithelial fates instead promotes differentiation. further provide mechanistic cues an association between epigenetic silencers lineage