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Histone Acetyltransferase KAT2A Stabilises Pluripotency with Control of Transcriptional Heterogeneity

View ORCID ProfileNaomi Moris, View ORCID ProfileShlomit Edri, View ORCID ProfileDenis Seyres, View ORCID ProfileRashmi Kulkarni, View ORCID ProfileAna Filipa Domingues, View ORCID ProfileTina Balayo, View ORCID ProfileMattia Frontini, View ORCID ProfileCristina Pina
doi: https://doi.org/10.1101/347476
Naomi Moris
1Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom;
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Shlomit Edri
1Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom;
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Denis Seyres
2Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, United Kingdom;
3National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, Cambridge CB2 0PT, UK;
4NIHR BioResource-Rare Diseases, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK;
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Rashmi Kulkarni
2Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, United Kingdom;
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Ana Filipa Domingues
2Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, United Kingdom;
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Tina Balayo
1Department of Genetics, University of Cambridge, Cambridge CB2 3EH, United Kingdom;
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Mattia Frontini
2Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, United Kingdom;
3National Health Service Blood and Transplant (NHSBT), Cambridge Biomedical Campus, Cambridge CB2 0PT, UK;
5BHF Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK;
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Cristina Pina
2Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0PT, United Kingdom;
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  • For correspondence: cp533@medschl.cam.ac.uk
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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 destabilisation 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) has been inhibited. Functionally, network destabilisation associates with reduced pluripotency and accelerated mesendodermal differentiation, with increased probability of transitions into lineage commitment. Thus, we functionally link transcriptional heterogeneity to cell fate transitions through manipulation of the histone acetylation landscape of mouse embryonic stem cells and establish a general paradigm that could be exploited in other normal and malignant stem cell fate transitions.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 14, 2018.
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Histone Acetyltransferase KAT2A Stabilises Pluripotency with Control of Transcriptional Heterogeneity
Naomi Moris, Shlomit Edri, Denis Seyres, Rashmi Kulkarni, Ana Filipa Domingues, Tina Balayo, Mattia Frontini, Cristina Pina
bioRxiv 347476; doi: https://doi.org/10.1101/347476
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Histone Acetyltransferase KAT2A Stabilises Pluripotency with Control of Transcriptional Heterogeneity
Naomi Moris, Shlomit Edri, Denis Seyres, Rashmi Kulkarni, Ana Filipa Domingues, Tina Balayo, Mattia Frontini, Cristina Pina
bioRxiv 347476; doi: https://doi.org/10.1101/347476

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