Metabolic Plasticity drives Development during Mammalian Embryogenesis

SummaryPreimplantation mouse embryos interact minimally with their environment, and development is largely driven by metabolic processes. During the earliest cleavage stages, metabolism is rigid, with maternal deposits enforcing a redox state that facilitates zygotic genome activation. As maternal control falls, metabolic shuttles are activated, increasing glycolysis and equilibrating the TCA cycle. The resulting flexibility of nutrient utilization and metabolic plasticity facilitates unidirectional developmental progression such that later stage embryos proceed to form blastocysts without any exogenously added nutrients. We explore the mechanisms that govern this choreographed sequence that balances the deposition, degradation, synthesis and function of metabolic enzymes with redox control, bioenergetics and biosynthesis. Cancer cells follow a distinct metabolic strategy from that of the preimplantation embryo. However, important shared features emerge under reductive stress. We conclude that metabolic plasticity drives normal development while stress conditions mimic hallmark events in Cancer Metabolism.

Development of mouse preimplantation embryos in space

The development of life beyond planet Earth is a long-standing quest of the human race, but whether normal mammalian embryonic development can occur in space is still unclear. Here, we show unequivocally that preimplantation mouse embryos can develop in space, but the rate of blastocyst formation and blastocyst quality are compromised. Additionally, the cells in the embryo contain severe DNA damage, while the genome of the blastocysts developed in space is globally hypomethylated with a unique set of differentially methylated regions. The developmental defects, DNA damage and epigenetic abnormalities can be largely mimicked by the treatment with ground-based low-dose radiation. However, the exposure to simulated microgravity alone does not cause major disruptions of embryonic development, indicating that radiation is the main cause for the developmental defects. This work advances the understanding of embryonic development in space and reveals long-term extreme low-dose radiation as a hazardous factor for mammalian reproduction.

A probabilistic framework for cellular lineage reconstruction using single-cell 5-hydroxymethylcytosine sequencing

Lineage reconstruction is central to understanding tissue development and maintenance. While powerful tools to infer cellular relationships have been developed, these methods typically have a clonal resolution that prevent the reconstruction of lineage trees at an individual cell division resolution. Moreover, these methods require a transgene, which poses a significant barrier in the study of human tissues. To overcome these limitations, we report scPECLR, a probabilistic algorithm to endogenously infer lineage trees at a single cell-division resolution using 5-hydroxymethylcytosine. When applied to 8-cell preimplantation mouse embryos, scPECLR predicts the full lineage tree with greater than 95% accuracy. Further, scPECLR can accurately extract lineage information for a majority of cells when reconstructing larger trees. Finally, we show that scPECLR can also be used to map chromosome strand segregation patterns during cell division, thereby providing a strategy to test the “immortal strand” hypothesis in stem cell biology. Thus, scPECLR provides a generalized method to endogenously reconstruct lineage trees at an individual cell-division resolution.