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IRF2 is a master regulator of human keratinocyte stem cell fate

Author

Listed:
  • 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
    Baylor College of Medicine)

  • Susan Kirkland

    (Novartis Pharma AG, Forum 1 Novartis Campus)

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.

Suggested Citation

  • Nicolas Mercado & Gabi Schutzius & Christian Kolter & David Estoppey & Sebastian Bergling & Guglielmo Roma & Caroline Gubser Keller & Florian Nigsch & Adrian Salathe & Remi Terranova & John Reece-Hoye, 2019. "IRF2 is a master regulator of human keratinocyte stem cell fate," Nature Communications, Nature, vol. 10(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12559-x
    DOI: 10.1038/s41467-019-12559-x
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