Abstract
BackgroundThere 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.ResultsUsing 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.ConclusionsThe 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.
Highlights
There is substantial interest in the evolutionary forces that shaped the regulatory framework in early human development
Study design and data collection in the Induced pluripotent stem cells (iPSCs)-based system To perform a comparative study of differentiated cells, we used a panel of six human and four chimpanzee iPSC lines previously derived and characterized by our lab [12, 13]
We differentiated the iPSCs into definitive endoderm, a process that was completed over three days [7], and included replicates of cell lines that were independently differentiated
Summary
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. It has been hypothesized that human-specific gene expression patterns in the brain might underlie functional, developmental, and perhaps cognitive differences between humans and other apes [2, 3]. Providing a measure of support for this notion, a recent comparative study that explored the temporal dynamics of gene regulation found potential differences in the timing of gene expression in the developing brain across primates [4]. Frozen post-mortem tissues are not optimal templates for many functional genomic assays; as a result, we lack datasets that survey multiple dimensions of gene regulatory mechanisms and
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