The default and directed pathways of hepatoblast differentiation involve distinct epigenomic mechanisms

The effectiveness of multiomics analyses in defining cell differentiation pathways during development is ambiguous. During liver development, hepatoblasts follow a default or directed pathway to differentiate into hepatocytes or cholangiocytes, respectively, and this provides a practical model to address this issue. Our study discovered that promoter-associated histone modifications and chromatin accessibility dynamics, rather than enhancer-associated histone modifications, effectively delineated the default vs. directedprocess of hepatoblast differentiation. Histone H3K27me3 on bivalent promoters is associated with this asymmetric differentiation strategy in mice and humans. We demonstrated that Ezh2 and Jmjd3 exert opposing regulatory roles in hepatoblast-cholangiocyte differentiation. Additionally, active enhancers, regulated by P300, correlate with the development of both hepatocytes and cholangiocytes. This research proposes a model highlighting the division of labor between promoters and enhancers, with promoter-associated chromatin modifications governing the default vs. directeddifferentiation mode of hepatoblasts, whereas enhancer-associated modifications primarily dictate the progressive development processes of hepatobiliary lineages.

Automated summary

The study reveals that promoter-associated histone modifications and chromatin accessibility dynamics effectively distinguish the default and directed processes of hepatoblast differentiation. The presence of H3K27me3 on bivalent promoters is associated with asymmetric differentiation strategy. The research also highlights the role of enhancer-associated modifications in the progressive development of hepatobiliary lineages.