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Elife. 2017 Oct 18;6. pii: e27356. doi: 10.7554/eLife.27356.

A protein phosphatase network controls the temporal and spatial dynamics of differentiation commitment in human epidermis.

Author information

1
Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom.
2
Department of Chemical Engineering and Biotechnology, Cambridge Infinitus Research Centre, University of Cambridge, Cambridge, United Kingdom.
3
Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
4
Wellcome Centre for Cell Biology, Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
5
Laboratory of Cerebral Physiology, Université Paris Descartes, Paris, France.
6
Microsoft Research, Cambridge, United Kingdom.
7
Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
#
Contributed equally

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.

KEYWORDS:

Boolean networks; commitment; computational biology; developmental biology; differentiation; epidermis; human; protein dephosphorylation; stem cells; systems biology

PMID:
29043977
PMCID:
PMC5667932
DOI:
10.7554/eLife.27356
[Indexed for MEDLINE]
Free PMC Article

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