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Genome Biol. 2018 Jan 15;19(1):3. doi: 10.1186/s13059-017-1384-y.

Epidermal Wnt signalling regulates transcriptome heterogeneity and proliferative fate in neighbouring cells.

Author information

1
The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
2
King's College London, Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
3
Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123, Torino, Italy.
4
The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. nicholas.luscombe@crick.ac.uk.
5
UCL Genetics Institute, University College London, London, WC1E 6BT, UK. nicholas.luscombe@crick.ac.uk.
6
Okinawa Institute of Science & Technology Graduate University, Okinawa, 904-0495, Japan. nicholas.luscombe@crick.ac.uk.
7
King's College London, Centre for Stem Cells and Regenerative Medicine, 28th Floor, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK. fiona.watt@kcl.ac.uk.

Abstract

BACKGROUND:

Canonical Wnt/beta-catenin signalling regulates self-renewal and lineage selection within the mammalian epidermis. Although the transcriptional response of keratinocytes that receive a Wnt signal is well characterized, little is known about the mechanism by which keratinocytes in proximity to the Wnt-receiving cell are co-opted to undergo a change in cell fate.

RESULTS:

To address this, we perform single-cell RNA-sequencing on mouse keratinocytes co-cultured with and without beta-catenin-activated neighbouring cells. We identify five distinct cell states in cultures that had not been exposed to the beta-catenin stimulus and show that the stimulus redistributes wild-type subpopulation proportions. Using temporal single-cell analysis, we reconstruct the cell fate change induced by Wnt activation from neighbouring cells. Gene expression heterogeneity is reduced in neighbouring cells and this effect is most dramatic for protein synthesis-associated genes. Changes in gene expression are accompanied by a shift to a more proliferative stem cell state. By integrating imaging and reconstructed sequential gene expression changes during the state transition we identify transcription factors, including Smad4 and Bcl3, that are responsible for effecting the transition in a contact-dependent manner.

CONCLUSIONS:

Our data indicate that non-cell autonomous Wnt/beta-catenin signalling decreases transcriptional heterogeneity. This furthers our understanding of how epidermal Wnt signalling orchestrates regeneration and self-renewal.

PMID:
29334988
PMCID:
PMC5769491
DOI:
10.1186/s13059-017-1384-y
[Indexed for MEDLINE]
Free PMC Article

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