Department of Animal Science and Reproductive and Developmental Sciences Program, Michigan State University, East Lansing, MI, USA.
Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, MI, USA.
Mol Hum Reprod. 2019 Mar 1;25(3):111-123. doi: 10.1093/molehr/gaz001.
The preimplantation period of life in mammals encompasses a tremendous amount of restructuring and remodeling of the embryonic genome and reprogramming of gene expression. These vast changes support metabolic activation and cellular processes that drive early cleavage divisions and enable the creation of the earliest primitive cell lineages. A major question in mammalian embryology is how such vast, sweeping changes in gene expression are orchestrated, so that changes in gene expression are exactly appropriate to meet the developmental needs of the embryo over time. Using the rhesus macaque as an experimentally tractable model species closely related to the human, we combined high quality RNA-seq libraries, in-depth sequencing and advanced systems analysis to discover the underlying mechanisms that drive major changes in gene regulation during preimplantation development. We identified the major changes in mRNA population and the biological pathways and processes impacted by those changes. Most importantly, we identified 24 key upstream regulators that are themselves modulated during development and that are associated with the regulation of over 1000 downstream genes. Through their roles in extensive gene networks, these 24 upstream regulators are situated to either drive major changes in target gene expression or modify the cellular environment in which other genes function, thereby directing major developmental transitions in the preimplantation embryo. The data presented here highlight some of the specific molecular features that likely drive preimplantation development in a nonhuman primate species and provides an extensive database for novel hypothesis-driven studies.
哺乳动物的着床前生命期涵盖了胚胎基因组的大量结构重组和重塑，以及基因表达的重新编程。这些巨大的变化支持代谢激活和细胞过程，推动早期分裂，并使最早的原始细胞谱系得以产生。哺乳动物胚胎学的一个主要问题是，如何协调如此广泛的基因表达变化，以便基因表达的变化恰好适应胚胎随时间推移的发育需求。我们使用与人类密切相关的实验上易于处理的恒河猴模型物种，结合高质量的 RNA-seq 文库、深度测序和先进的系统分析，来发现驱动着床前发育过程中基因调控的主要变化的潜在机制。我们确定了 mRNA 群体的主要变化，以及受这些变化影响的生物学途径和过程。最重要的是，我们确定了 24 个关键的上游调节剂，它们在发育过程中本身会被调节，并与超过 1000 个下游基因的调节相关。通过它们在广泛的基因网络中的作用，这些 24 个上游调节剂可以驱动靶基因表达的重大变化，或者改变其他基因发挥功能的细胞环境，从而指导着床前胚胎的重大发育转变。这里呈现的数据突出了一些可能在非人类灵长类动物物种中驱动着床前发育的特定分子特征，并为新的基于假说的研究提供了广泛的数据库。
