098 Chromatin architectural protein CTCF controls keratinocyte differentiation, barrier maintenance and suppresses inflammation and tumorigenesis in the epidermis

Epigenetic regulatory mechanisms and spatial chromatin interactions in the nucleus involving gene promoters and distal regulatory/enhancer elements are currently considered as one of the major forces that define cell identity and drive differentiation process, while such interactions are substantially re-organized and contribute to the development of many pathological conditions, including cancer. Chromatin architectural protein CTCF controls the establishment and maintenance of the long-range enhancer/promoter regulatory networks in differentiating cells. To study the role of CTCF in the control of epidermal development, genetically engineered mice with conditional Ctcf ablation under control of the Keratin 14 promoter (K14-CreER/Ctcf fl/fl) were generated. Ctcf ablation in adlut mice resulted in marked increase of the epidermal thickness, expansion of proliferating keratinocytes into the suprabasal epidermal layers, and in alterations in the expression of terminal differentiation-associated genes. These changes were accompanied by perturbations of the epidermal barrier structure followed by infiltration of the epidermis by immune cells, as well as by the rapid progression of the epidermal inflammation towards the development of squamous papilloma-like tumours. Microarray analyses of the laser-captured epidermis of K14-CreER/Ctcf fl/fl mice showed alterations in expression of the genes involved in the control of terminal keratinocyte differentiation, cell cycle regulation, immune response and tumorigenesis, while ChIP-seq analyses revealed predominance of the CTCF binding to the distal gene regulatory elements versus gene promoters in epidermal keratinocytes. Thus, these data suggest that CTCF plays pivotal roles in the control of epidermal differentiation and barrier maintenance, as well as operates as a potent suppressor of the epidermal inflammatory responses and tumorigenesis in adult skin.