Department of Human Genetics, University of Chicago, Chicago, IL, USA.
Department of Medicine, University of Chicago, Chicago, IL, USA.
Genome Biol. 2018 Oct 15;19(1):162. doi: 10.1186/s13059-018-1490-5.
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.
人们对塑造早期人类发育调控框架的进化力量有着浓厚的兴趣。由于难以获得相关的生物样本，该领域的进展一直较为缓慢。诱导多能干细胞（iPSC）可能提供建立人类和非人类灵长类动物早期发育阶段体外模型的能力。
使用来自人类和黑猩猩的匹配 iPSC 面板，我们通过 iPSC 向原条、内胚层祖细胞和确定的内胚层分化的为期四天的时间过程比较地描述了基因调控变化。正如预期的那样，我们发现分化阶段是基因表达水平变化的主要驱动因素，其次是物种。我们在每个分化阶段都鉴定了人类和黑猩猩之间数千个差异表达的基因。然而，当我们考虑整个时间过程中基因特异性的动态调控轨迹时，我们发现至少 75%的基因，包括几乎所有已知的内胚层发育标记物，在两个物种中具有相似的轨迹。有趣的是，与 iPSC 相比，在原始条带样本中观察到基因表达水平的内源性和种间变异明显减少，而在内胚层祖细胞中恢复了调控变异。
在特定发育阶段基因表达水平的变异减少，加上时间基因调控的整体高度保守性，与保守的发育过程的动态相一致。
