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

Abstract

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.

Authors:
ORCiD logo [1]; ORCiD logo [1];  [1]; ORCiD logo [1];  [1];  [1];  [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1];  [1];  [1]
  1. Univ. of California, Santa Barbara, CA (United States)
Publication Date:
Research Org.:
Univ. of California, Santa Barbara, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1611177
Grant/Contract Number:  
SC0008975
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Biology (Online)
Additional Journal Information:
Journal Name: PLoS Biology (Online); Journal Volume: 17; Journal Issue: 9; Journal ID: ISSN 1545-7885
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics

Citation Formats

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., and Brickman, Joshua Mark. Control over single-cell distribution of G1 lengths by WNT governs pluripotency. United States: N. p., 2019. Web. https://doi.org/10.1371/journal.pbio.3000453.
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. Control over single-cell distribution of G1 lengths by WNT governs pluripotency. United States. https://doi.org/10.1371/journal.pbio.3000453
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., and Brickman, Joshua Mark. Thu . "Control over single-cell distribution of G1 lengths by WNT governs pluripotency". United States. https://doi.org/10.1371/journal.pbio.3000453. https://www.osti.gov/servlets/purl/1611177.
@article{osti_1611177,
title = {Control over single-cell distribution of G1 lengths by WNT governs pluripotency},
author = {Jang, Jiwon and Han, Dasol and Golkaram, Mahdi and Audouard, Morgane and Liu, Guojing and Bridges, Daniel and Hellander, Stefan and Chialastri, Alex and Dey, Siddharth S. and Petzold, Linda R. and Kosik, Kenneth S. and Brickman, Joshua Mark},
abstractNote = {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.},
doi = {10.1371/journal.pbio.3000453},
journal = {PLoS Biology (Online)},
number = 9,
volume = 17,
place = {United States},
year = {2019},
month = {9}
}

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