IRF2 is a master regulator of human keratinocyte stem cell fate

Nicolas Mercado, Gabi Schutzius, Christian Kolter, David Estoppey, Sebastian Bergling, Guglielmo Roma, Caroline Gubser Keller, Florian Nigsch, Adrian Salathe, Remi Terranova, John Reece-Hoyes, John Alford, Carsten Russ, Judith Knehr, Dominic Hoepfner, Alexandra Aebi, Heinz Ruffner, Tanner C. Beck, Sajjeev Jagannathan, Calla M. Olson, Hadley E. Sheppard, Selma Z. Elsarrag, Tewis Bouwmeester, Mathias Frederiksen, Felix Lohmann (), Charles Y. Lin () and Susan Kirkland ()
Additional contact information
Nicolas Mercado: Novartis Pharma AG, Forum 1 Novartis Campus
Gabi Schutzius: Novartis Pharma AG, Forum 1 Novartis Campus
Christian Kolter: Novartis Pharma AG, Forum 1 Novartis Campus
David Estoppey: Novartis Pharma AG, Forum 1 Novartis Campus
Sebastian Bergling: Novartis Pharma AG, Forum 1 Novartis Campus
Guglielmo Roma: Novartis Pharma AG, Forum 1 Novartis Campus
Caroline Gubser Keller: Novartis Pharma AG, Forum 1 Novartis Campus
Florian Nigsch: Novartis Pharma AG, Forum 1 Novartis Campus
Adrian Salathe: Novartis Pharma AG, Forum 1 Novartis Campus
Remi Terranova: Translational Medicine, NIBR
John Reece-Hoyes: Novartis Institutes for Biomedical Research
John Alford: Novartis Institutes for Biomedical Research
Carsten Russ: Novartis Institutes for Biomedical Research
Judith Knehr: Novartis Pharma AG, Forum 1 Novartis Campus
Dominic Hoepfner: Novartis Pharma AG, Forum 1 Novartis Campus
Alexandra Aebi: Novartis Pharma AG, Forum 1 Novartis Campus
Heinz Ruffner: Novartis Pharma AG, Forum 1 Novartis Campus
Tanner C. Beck: Baylor College of Medicine
Sajjeev Jagannathan: Baylor College of Medicine
Calla M. Olson: Baylor College of Medicine
Hadley E. Sheppard: Baylor College of Medicine
Selma Z. Elsarrag: Baylor College of Medicine
Tewis Bouwmeester: Novartis Pharma AG, Forum 1 Novartis Campus
Mathias Frederiksen: Novartis Pharma AG, Forum 1 Novartis Campus
Felix Lohmann: Transplantation and Inflammation, NIBR
Charles Y. Lin: Baylor College of Medicine
Susan Kirkland: Novartis Pharma AG, Forum 1 Novartis Campus

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract Resident adult epithelial stem cells maintain tissue homeostasis by balancing self-renewal and differentiation. The stem cell potential of human epidermal keratinocytes is retained in vitro but lost over time suggesting extrinsic and intrinsic regulation. Transcription factor-controlled regulatory circuitries govern cell identity, are sufficient to induce pluripotency and transdifferentiate cells. We investigate whether transcriptional circuitry also governs phenotypic changes within a given cell type by comparing human primary keratinocytes with intrinsically high versus low stem cell potential. Using integrated chromatin and transcriptional profiling, we implicate IRF2 as antagonistic to stemness and show that it binds and regulates active cis-regulatory elements at interferon response and antigen presentation genes. CRISPR-KD of IRF2 in keratinocytes with low stem cell potential increases self-renewal, migration and epidermis formation. These data demonstrate that transcription factor regulatory circuitries, in addition to maintaining cell identity, control plasticity within cell types and offer potential for therapeutic modulation of cell function.

Date: 2019
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DOI: 10.1038/s41467-019-12559-x

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