Single-cell multiome uncovers differences in glycogen metabolism underlying species-specific speed of development

Embryos from different mammalian species develop at characteristic timescales. These timescales are recapitulated during the differentiation of pluripotent stem cells in vitro . Specific genes and molecular pathways that modulate cell differentiation speed between mammalian species remain to be determined. Here we use single-cell multi-omic analysis of neural differentiation of mouse, cynomolgus and human pluripotent cells to identify regulators for differentiation speed. We demonstrate that species-specific transcriptome dynamics are mirrored at the chromatin level, but that the speed of neural differentiation is insensitive to manipulations of cell growth and cycling. Exploiting the single-cell resolution of our data, we identify glycogen storage levels regulated by UDP-glucose pyrophosphorylase 2 (UGP2) as a species-dependent trait of pluripotent cells, and show that lowered glycogen storage in UGP2 mutant cells is associated with accelerated neural differentiation. The control of energy storage could be a general strategy for the regulation of cell differentiation speed.