Histone Acetyltransferase KAT2A Stabilizes Pluripotency with Control of Transcriptional Heterogeneity.
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Authors
Kulkarni, Rashmi
Domingues, Ana Filipa
Balayo, Tina
Publication Date
2018-12Journal Title
Stem Cells
ISSN
1066-5099
Publisher
Oxford University Press (OUP)
Volume
36
Issue
12
Pages
1828-1838
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Moris, N., Edri, S., Seyres, D., Kulkarni, R., Domingues, A. F., Balayo, T., Frontini, M., & et al. (2018). Histone Acetyltransferase KAT2A Stabilizes Pluripotency with Control of Transcriptional Heterogeneity.. Stem Cells, 36 (12), 1828-1838. https://doi.org/10.1002/stem.2919
Abstract
Cell fate transitions in mammalian stem cell systems have often been associated with transcriptional heterogeneity; however, existing data have failed to establish a functional or mechanistic link between the two phenomena. Experiments in unicellular organisms support the notion that transcriptional heterogeneity can be used to facilitate adaptability to environmental changes and have identified conserved chromatin-associated factors that modulate levels of transcriptional noise. Herein, we show destabilization of pluripotency-associated gene regulatory networks through increased transcriptional heterogeneity of mouse embryonic stem cells in which paradigmatic histone acetyl-transferase, and candidate noise modulator, Kat2a (yeast orthologue Gcn5), have been inhibited. Functionally, network destabilization associates with reduced pluripotency and accelerated mesendodermal differentiation, with increased probability of transitions into lineage commitment. Thus, we show evidence of a relationship between transcriptional heterogeneity and cell fate transitions through manipulation of the histone acetylation landscape of mouse embryonic stem cells, suggesting a general principle that could be exploited in other normal and malignant stem cell fate transitions. Stem Cells 2018;36:1828-11.
Keywords
Pluripotent Stem Cells, Animals, Humans, Mice, Cell Differentiation, Genetic Heterogeneity, Histone Acetyltransferases
Sponsorship
Wellcome Trust, BBSRC, Isaac Newton Trust, Kay Kendall Leukaemia Fund, Leuka, British Heart Foundation
Funder references
Biotechnology and Biological Sciences Research Council (BB/J014540/1)
British Heart Foundation (None)
Kay Kendall Leukaemia Fund (KKL888)
Isaac Newton Trust (17.07(f))
Leuka (unknown)
BBSRC (1221216)
European Commission FP7 Network of Excellence (NoE) (282510)
Identifiers
External DOI: https://doi.org/10.1002/stem.2919
This record's URL: https://www.repository.cam.ac.uk/handle/1810/282850
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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