Laser capture and deep sequencing reveals the transcriptomic programmes regulating the onset of pancreas and liver differentiation in human embryos

To interrogate the alternative fates of pancreas and liver in the earliest stages of human organogenesis we developed laser capture, RNA amplification and computational analysis of deep sequencing. Pancreas-enriched gene expression was less conserved between human and mouse than for liver. The dorsal pancreatic bud was enriched for components of Notch, Wnt, BMP and FGF signalling, almost all genes known to cause pancreatic agenesis or hypoplasia, and over 30 unexplored transcription factors. SOX9 and RORA were imputed as key regulators in pancreas compared to EP300, HNF4A and FOXA family members in liver. Analyses implied that current in vitro human stem cell differentiation follows a dorsal rather than a ventral pancreatic programme and pointed to new factors for hepatic differentiation. In summary, we provide the first transcriptional codes regulating the start of human liver and pancreas development to facilitate stem cell research and clinical interpretation without inter-species extrapolation.