Department of Biochemistry and Molecular Biology, Paul D. Coverdell Center for Biomedical and Health Sciences, The University of Georgia, 500 D.W. Brooks Drive, Athens, GA 30602, USA.
Department of Human Genetics, Emory University, 615 Michael Street, Atlanta, GA 30322, USA.
Stem Cell Reports. 2013 Dec 5;1(6):532-44. doi: 10.1016/j.stemcr.2013.10.009. eCollection 2013.
Heterogeneity within pluripotent stem cell (PSC) populations is indicative of dynamic changes that occur when cells drift between different states. Although the role of metastability in PSCs is unclear, it appears to reflect heterogeneity in cell signaling. Using the Fucci cell-cycle indicator system, we show that elevated expression of developmental regulators in G1 is a major determinant of heterogeneity in human embryonic stem cells. Although signaling pathways remain active throughout the cell cycle, their contribution to heterogeneous gene expression is restricted to G1. Surprisingly, we identify dramatic changes in the levels of global 5-hydroxymethylcytosine, an unanticipated source of epigenetic heterogeneity that is tightly linked to cell-cycle progression and the expression of developmental regulators. When we evaluated gene expression in differentiating cells, we found that cell-cycle regulation of developmental regulators was maintained during lineage specification. Cell-cycle regulation of developmentally regulated transcription factors is therefore an inherent feature of the mechanisms underpinning differentiation.
多能干细胞 (PSC) 群体中的异质性表明细胞在不同状态之间漂移时会发生动态变化。尽管在 PSCs 中，亚稳性的作用尚不清楚，但它似乎反映了细胞信号转导的异质性。使用 Fucci 细胞周期指示剂系统，我们表明 G1 中发育调节剂的高表达是人类胚胎干细胞异质性的主要决定因素。尽管信号通路在整个细胞周期中仍然活跃，但它们对异质基因表达的贡献仅限于 G1。令人惊讶的是，我们发现 5-羟甲基胞嘧啶的水平发生了显著变化，这是一种意外的表观遗传异质性来源，与细胞周期进程和发育调节剂的表达密切相关。当我们评估分化细胞中的基因表达时，我们发现发育调节剂的细胞周期调控在谱系特化过程中得以维持。因此，发育调节转录因子的细胞周期调控是分化机制的固有特征。
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