A comparative study of endoderm differentiation in humans and chimpanzees

There is substantial interest in the evolutionary forces that shaped the regulatory framework in early human development. Progress in this area has been slow because it is difficult to obtain relevant biological samples. Induced pluripotent stem cells (iPSCs) may provide the ability to establish in vitro models of early human and non-human primate developmental stages.

Using matched iPSC panels from humans and chimpanzees, we comparatively characterize gene regulatory changes through a four-day time course differentiation of iPSCs into primary streak, endoderm progenitors, and definitive endoderm. As might be expected, we find that differentiation stage is the major driver of variation in gene expression levels, followed by species. We identify thousands of differentially expressed genes between humans and chimpanzees in each differentiation stage. Yet, when we consider gene-specific dynamic regulatory trajectories throughout the time course, we find that at least 75% of genes, including nearly all known endoderm developmental markers, have similar trajectories in the two species. Interestingly, we observe a marked reduction of both intra- and inter-species variation in gene expression levels in primitive streak samples compared to the iPSCs, with a recovery of regulatory variation in endoderm progenitors.

The reduction of variation in gene expression levels at a specific developmental stage, paired with overall high degree of conservation of temporal gene regulation, is consistent with the dynamics of a conserved developmental process.