TBX3 advances the developmental chromatin landscape toward the hepatic fate

By mapping histone modifications in a human stem cell model of hepatic differentiation, we identified an enhancer landscape that is dynamic and stage specific, with many primed at the definitive endoderm stage. While hepatic enhancers gained active histone modifications, non-hepatic enhancers lost H3K4me1 after hepatic specification. T-box transcription factor 3 (TBX3) was found to bind to hepatic enhancers and promoters. TBX3 binding was transient, and only upon the dissociation of TBX3 from its bound regions were active histone modifications acquired. Subsequently, transcription was activated, supporting a role for TBX3 in directly activating the hepatic lineage. Constitutive overexpression of TBX3 indicated that dissociation of TBX3 is crucial for gene activation. TBX3 did not bind to any pancreatic regulatory regions directly, indicating indirect repression of the pancreatic lineage. Together, this suggests that TBX3 plays a role in identifying and bookmarking hepatic enhancers and promoters during specification, which subsequently will be activated to drive cell identity.