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Pancreatic and Duodenal Homeobox 1 (PDX1) encodes a homeobox transcription factor that is expressed at the earliest stages of human embryonic pancreatic development.Lineage tracing studies in the mouse have conclusively shown that Pdx1 + early pancreatic progenitor (ePP) cells are multipotent, giving rise to the exocrine,endocrine and ductal components of the adult organ.Consistent with this, loss of Pdx1 results in complete pancreatic agenesis both in mice and in man.This catastrophic phenotype clearly indicates that Pdx1 sits high atop the gene regulatory network that orchestrates the morphogenesis of this indispensible endocrine organ.However, little is known about the identity of PDX1 transcriptional targets.We simulated pancreatic development by differentiating human embryonic stem cells (hESCs) into early pancreatic progenitors and subjected this cell population to PDX1 chromatin immunoprecipitation sequencing (ChIP-seq).We identified more than 350 genes bound by PDX1, whose expression was upregulated on day 17 of differentiation.This group included known PDX1 targets and many genes not previously linked to pancreatic development.ChIP-seq also surprisingly revealed PDX1 occupancy at hepatic genes.We hypothesized that simultaneous PDX1-driven activation of pancreatic and repression of hepatic programs underlie early divergence between pancreas and liver.In HepG2 cells and differentiating hESCs, we found that PDX1 binds and suppresses expression of endogenous liver genes.These findings rebrand PDX1 as a context-dependent transcriptional repressor and activator within the same cell type.