Journal Article

IRF2 is a master regulator of human keratinocyte stem cell fate

Mercado, Nicolas, Hoepfner, Dominic, Knehr, Judith, Elsarrag, Selma Z., Roma, Guglielmo, Schutzius, Gabi, Gubser Keller, Caroline, Alford, John, Bergling, Sebastian, Aebi, Alexandra, Ruffner, Heinz, Nigsch, Florian, Salathe, Adrian, Estoppey, David, Lin, Charles Y., Terranova, Remi, Jagannathan, Sajjeev, Frederiksen, Mathias, Russ, Carsten, Lohmann, Felix, Kolter, Christian, Kirkland, Susan, Beck, Tanner C., Sheppard, Hadley E., Olson, Calla M., Bouwmeester, Tewis, Reece-Hoyes, John

2019

Overview

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. Epidermal homeostasis requires long term stem cell function. Here, the authors apply transcriptional circuitry analysis based on integrated epigenomic profiling of primary human keratinocytes with high and low stem cell function to identify IRF2 as a negative regulator of stemness.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/100 / 13/106 / 13/44 / 38/109 / 38/15 / 38/39 / 38/79 / 38/90 / 38/91 / 45/15 / 631/114/2114 / 631/532/2438 / 631/532/2441 / 631/532/489 / 82/29 / 82/80 / Antigen presentation / Antigens / Cell differentiation / Cell Differentiation - genetics / Cell Differentiation - physiology / Cell fate / Cell self-renewal / Chromatin / Circuits / CRISPR / Epidermis / Gene regulation / Homeostasis / Humanities and Social Sciences / Humans / Interferon / Interferon Regulatory Factor-2 - genetics / Interferon Regulatory Factor-2 - metabolism / Keratinocytes / Keratinocytes - cytology / Keratinocytes - metabolism / multidisciplinary / Pluripotency / Regulatory sequences / Science / Science (multidisciplinary) / Stem cells / Stem Cells - cytology / Stem Cells - metabolism / Transcription factors / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptional Activation - genetics / Transcriptional Activation - physiology