Flux balance network expansion predicts stage-specific human peri_implantation embryo metabolism

Abstract

Metabolism is an essential cellular process for the growth and maintenance of organisms. A better understanding of metabolism during embryogenesis may shed light on the developmental origins of human disease. Metabolic networks, however, are vastly complex with many redundant pathways and interconnected circuits. Thus, computational approaches serve as a practical solution for unraveling the genetic basis of embryo metabolism to help guide future experimental investigations. RNA-sequencing and other profiling technologies make it possible to elucidate metabolic genotype–phenotype relationships and yet our understanding of metabolism is limited. Very few studies have examined the temporal or spatial metabolomics of the human embryo, and prohibitively small sample sizes traditionally observed in human embryo research have presented logistical challenges for metabolic studies, hindering progress towards the reconstruction of the human embryonic metabolome. We employed a network expansion algorithm to evolve the metabolic network of the peri-implantation embryo metabolism and we utilized flux balance analysis (FBA) to examine the viability of the evolved networks. We found that modulating oxygen uptake promotes lactate diffusion across the outer mitochondrial layer, providing in-silico support for a proposed lactate–malate–aspartate shuttle. We developed a stage-specific model to serve as a proof-of-concept for the reconstruction of future metabolic models of development. Our work shows that it is feasible to model human metabolism with respect to time-dependent changes characteristic of peri-implantation development.