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

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.; Brickman, Joshua Mark

doi:10.1371/journal.pbio.3000453

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

Journal Article · 26 September 2019 · PLoS Biology (Online)

DOI: https://doi.org/10.1371/journal.pbio.3000453 · OSTI ID:1611177

^[1];

^[2]; Golkaram, Mahdi ^[2];

^[2]; Liu, Guojing ^[2]; Bridges, Daniel ^[2]; Hellander, Stefan ^[2];

^[2];

^[2]; Kosik, Kenneth S. ^[2]; Brickman, Joshua Mark ^[2]

Univ. of California, Santa Barbara, CA (United States); DOE/OSTI
Univ. of California, Santa Barbara, CA (United States)

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.

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Research Organization:: Univ. of California, Santa Barbara, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0008975

OSTI ID:: 1611177

Journal Information:: PLoS Biology (Online), Journal Name: PLoS Biology (Online) Journal Issue: 9 Vol. 17; ISSN 1545-7885

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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