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Nat Commun. 2019 Oct 14;10(1):4676. doi: 10.1038/s41467-019-12559-x.

IRF2 is a master regulator of human keratinocyte stem cell fate.

Author information

1
Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland.
2
Preclinical Safety, Translational Medicine, NIBR, Basel, CH-4057, Switzerland.
3
Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
4
Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.
6
Autoimmunity, Transplantation and Inflammation, NIBR, Basel, CH-4056, Switzerland. Felix.Lohmann@novartis.com.
7
Therapeutic Innovation Center, Department of Biochemistry and Molecular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. Charles.Y.Lin@bcm.edu.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA. Charles.Y.Lin@bcm.edu.
9
Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056, Basel, Switzerland. Susan.Kirkland@novartis.com.

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.

PMID:
31611556
PMCID:
PMC6791852
DOI:
10.1038/s41467-019-12559-x
[Indexed for MEDLINE]
Free PMC Article

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