A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
- King's College London, United Kingdom
- University of Dundee, United Kingdom
- Microsoft Research, United Kingdom
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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Funding
Wellcome Trust (096540/Z/11/Z)
- Benedicte Oules
- Kifayathullah Liakath-Ali
- Gernot Walko
- Priyalakshmi Viswanathan
- Jagdeesh Nijjher
- Sara-Jane Dunn
- Angus I Lamond
- Fiona M Watt
Medical Research Council (G1100073)
- Angela Oliveira Pisco
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Mishra et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis
eLife 6:e27356.
https://doi.org/10.7554/eLife.27356
