Single-cell multiome uncovers differences in glycogen metabolism underlying species-specific speed of development [UGP2 KO]. Single-cell multiome uncovers differences in glycogen metabolism underlying species-specific speed of development [UGP2 KO]

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 identified. Here we use single-cell multi-omic analysis of neural differentiation of mouse, cynomolgus monkey and human pluripotent cells to identify new regulators for differentiation speed. We demonstrate that species-specific differences in transcriptome dynamics are mirrored at the chromatin level, but that, contrary to other developmental contexts, 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 UGP2 expression as a new species-specific 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. Overall design: Neural differentiation of a UGP2 KO lines was performed with sequencing samples collected at 0 hours and 7 days post-induction.

不同哺乳动物物种的胚胎发育均具有各自的特征性时间尺度。此类发育时间尺度可在体外多能干细胞（pluripotent stem cell）的分化过程中重现。目前，调控哺乳动物物种间细胞分化速度的特定基因与分子通路仍有待鉴定。本研究通过对小鼠、食蟹猴（cynomolgus monkey）及人类多能干细胞的神经分化开展单细胞多组学（single-cell multi-omic）分析，以筛选调控分化速度的新型调控因子。研究证实，物种特异性的转录组动力学差异在染色质层面也得到了印证；但与其他发育场景不同的是，神经分化速度不受细胞生长与细胞周期调控操作的影响。借助本研究数据的单细胞分辨率，我们鉴定出受UGP2表达调控的糖原储存水平，是多能干细胞的一种新型物种特异性特征；同时发现UGP2突变细胞中糖原储存水平降低，与神经分化加速密切相关。能量储存的调控或为调控细胞分化速度的通用策略。实验设计：对UGP2敲除细胞系开展神经分化实验，分别在诱导后0小时与7天收集测序样本。