Control over single-cell distribution of G1 lengths by WNT governs pluripotency

• Published in: PLoS biology Vol. 17; no. 9; p. e3000453
• Main Authors: Jang, Jiwon, Han, Dasol, Golkaram, Mahdi, Audouard, Morgane, Liu, Guojing, Bridges, Daniel, Hellander, Stefan, Chialastri, Alex, Dey, Siddharth S, Petzold, Linda R, Kosik, Kenneth S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26-09-2019; Public Library of Science (PLoS)
• Subjects: 60 APPLIED LIFE SCIENCES; Analysis; Biochemistry & Molecular Biology; Biology and Life Sciences; Cell cycle; Cell Differentiation; Cell division; Cell Line; Chemical engineering; Computer science; Developmental biology; Differentiation; Embryo cells; Embryonic stem cells; Embryonic Stem Cells - physiology; Embryos; Funding; G1 Phase; Gene expression; Genetic variation; Genomes; Heterogeneity; Humans; Level (quantity); Life Sciences & Biomedicine - Other Topics; Mechanical engineering; Medicine and Health Sciences; Mesendoderm; Neuroectoderm; Neurosciences; Pluripotency; Population; Populations; Priming; Probability distribution; Stem cells; Variation; Wnt protein; Wnt Proteins - physiology; United States; United States > US; Santa Barbara California; California
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3000453

The link between single-cell variation and population-level fate choices lacks a mechanistic explanation despite extensive observations of gene expression and epigenetic variation among individual cells. Here, we found that single human embryonic stem cells (hESCs) have different and biased differentiation potentials toward either neuroectoderm or mesendoderm depending on their G1 lengths before the onset of differentiation. Single-cell variation in G1 length operates in a dynamic equilibrium that establishes a G1 length probability distribution for a population of hESCs and predicts differentiation outcome toward neuroectoderm or mesendoderm lineages. Although sister stem cells generally share G1 lengths, a variable proportion of cells have asymmetric G1 lengths, which maintains the population dispersion. Environmental Wingless-INT (WNT) levels can control the G1 length distribution, apparently as a means of priming the fate of hESC populations once they undergo differentiation. As a downstream mechanism, global 5-hydroxymethylcytosine levels are regulated by G1 length and thereby link G1 length to differentiation outcomes of hESCs. Overall, our findings suggest that intrapopulation heterogeneity in G1 length underlies the pluripotent differentiation potential of stem cell populations.