A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states, termed commitment, is poorly understood. Here, we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension to induce differentiation. Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA - promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression antagonises commitment. The phosphatases form a dynamic network of transient positive and negative interactions that change over time, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem and differentiated) via an unstable (committed) state. Phosphatase expression is also spatially regulated in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.
Cell Differentiation, Cells, Cultured, Gene Expression Profiling, Gene Expression Regulation, Humans, Keratinocytes/enzymology, Phosphoprotein Phosphatases/metabolism, Proteome/analysis
Mishra, Ajay
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Oulès, Bénédicte
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Pisco, Angela Oliveira
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Ly, Tony
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Liakath-Ali, Kifayathullah
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Walko, Gernot
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Viswanathan, Priyalakshmi
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Tihy, Matthieu
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Nijjher, Jagdeesh
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Dunn, Sara-Jane
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Lamond, Angus I.
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Watt, Fiona M.
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2 November 2017
Mishra, Ajay
d7ab328b-f7b9-4985-8be7-24f90228bba9
Oulès, Bénédicte
23b8289f-14a3-4b71-8216-744e0d623202
Pisco, Angela Oliveira
704ee75d-8a49-434a-8f5c-cad62d4036af
Ly, Tony
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Liakath-Ali, Kifayathullah
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Walko, Gernot
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Viswanathan, Priyalakshmi
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Tihy, Matthieu
3a227634-f39d-400f-afd2-07ba31599f21
Nijjher, Jagdeesh
d01c132e-f15a-45bd-96fe-df7861df365e
Dunn, Sara-Jane
95829b9e-ef85-4b1a-baba-b2dcc88c40f7
Lamond, Angus I.
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Watt, Fiona M.
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Mishra, Ajay, Oulès, Bénédicte, Pisco, Angela Oliveira, Ly, Tony, Liakath-Ali, Kifayathullah, Walko, Gernot, Viswanathan, Priyalakshmi, Tihy, Matthieu, Nijjher, Jagdeesh, Dunn, Sara-Jane, Lamond, Angus I. and Watt, Fiona M.
(2017)
A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis.
eLife, 6, [e27356].
(doi:10.7554/eLife.27356).
Abstract
Epidermal homeostasis depends on a balance between stem cell renewal and terminal differentiation. The transition between the two cell states, termed commitment, is poorly understood. Here, we characterise commitment by integrating transcriptomic and proteomic data from disaggregated primary human keratinocytes held in suspension to induce differentiation. Cell detachment induces several protein phosphatases, five of which - DUSP6, PPTC7, PTPN1, PTPN13 and PPP3CA - promote differentiation by negatively regulating ERK MAPK and positively regulating AP1 transcription factors. Conversely, DUSP10 expression antagonises commitment. The phosphatases form a dynamic network of transient positive and negative interactions that change over time, with DUSP6 predominating at commitment. Boolean network modelling identifies a mandatory switch between two stable states (stem and differentiated) via an unstable (committed) state. Phosphatase expression is also spatially regulated in vivo and in vitro. We conclude that an auto-regulatory phosphatase network maintains epidermal homeostasis by controlling the onset and duration of commitment.
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elife-27356-v2
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Accepted/In Press date: 10 October 2017
e-pub ahead of print date: 18 October 2017
Published date: 2 November 2017
Keywords:
Cell Differentiation, Cells, Cultured, Gene Expression Profiling, Gene Expression Regulation, Humans, Keratinocytes/enzymology, Phosphoprotein Phosphatases/metabolism, Proteome/analysis
Identifiers
Local EPrints ID: 491581
URI: http://eprints.soton.ac.uk/id/eprint/491581
ISSN: 2050-084X
PURE UUID: d604bc82-129d-438c-a2cd-b3bd6763c75c
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Date deposited: 27 Jun 2024 16:37
Last modified: 28 Jun 2024 02:09
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Contributors
Author:
Ajay Mishra
Author:
Bénédicte Oulès
Author:
Angela Oliveira Pisco
Author:
Tony Ly
Author:
Kifayathullah Liakath-Ali
Author:
Gernot Walko
Author:
Priyalakshmi Viswanathan
Author:
Matthieu Tihy
Author:
Jagdeesh Nijjher
Author:
Sara-Jane Dunn
Author:
Angus I. Lamond
Author:
Fiona M. Watt
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