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.
Data availability
Article and author information
Author details
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.
Reviewing Editor
- Valerie Horsley, Yale University, United States
Publication history
- Received: April 1, 2017
- Accepted: October 10, 2017
- Accepted Manuscript published: October 18, 2017 (version 1)
- Version of Record published: November 2, 2017 (version 2)
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.
Metrics
-
- 3,076
- Page views
-
- 632
- Downloads
-
- 26
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Computational and Systems Biology
- Evolutionary Biology
Using a neural network to predict how green fluorescent proteins respond to genetic mutations illuminates properties that could help design new proteins.
-
- Computational and Systems Biology
- Genetics and Genomics
Thermal adaptation is an extensively used intervention for enhancing or suppressing thermogenic and mitochondrial activity in adipose tissues. As such, it has been suggested as a potential lifestyle intervention for body weight maintenance. While the metabolic consequences of thermal acclimation are not limited to the adipose tissues, the impact on the rest of the tissues in context of their gene expression profile remains unclear. Here, we provide a systematic characterization of the effects in a comparative multi-tissue RNA sequencing approach following exposure of mice to 10 °C, 22 °C, or 34 °C in a panel of organs consisting of spleen, bone marrow, spinal cord, brain, hypothalamus, ileum, liver, quadriceps, subcutaneous-, visceral- and brown adipose tissues. We highlight that transcriptional responses to temperature alterations exhibit a high degree of tissue-specificity both at the gene level and at GO enrichment gene sets, and show that the tissue-specificity is not directed by the distinct basic gene expression pattern exhibited by the various organs. Our study places the adaptation of individual tissues to different temperatures in a whole-organism framework and provides integrative transcriptional analysis necessary for understanding the temperature-mediated biological programming.
