IRF2 is a master regulator of human keratinocyte stem cell fate [ChIPmentation]

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