TBX3 advances the developmental chromatin landscape towards the hepatic fate [RNA-seq II]

Hepatocytes differentiate from definitive endoderm in response to external signaling cues, however it is unclear how the hepatic lineage is specified and how transcription factors shape the chromatin to allow gene expression. By mapping histone modifications using a human stem cell model of hepatic differentiation, enhancers were found to exhibit dynamic, stage specific regulation, with many primed at the definitive endoderm stage. While hepatic enhancers gained active histone modifications, non-hepatic enhancers lost H3K4me1 after hepatic specification. TBX3, and to lesser extend HNF4A, bound to the hepatic enhancers and formed an interdependent transcription factor network. TBX3 bound both hepatic enhancers and promoters with low levels of H3K4me1 and a strong TBX3 motif. However, TBX3 binding was transient and upon eviction from TBX3-bound regions, H3K4me1 increased at enhancers, while H3K4me3 was established at promoters. This suggests that TBX3 plays a role in identifying hepatic enhancers and promoters during specification, which will then be activated to drive cell idenity.