076 Chromatin architectural protein CTCF controls terminal keratinocyte differentiation, epidermal barrier maintenance and suppresses inflammatory responses in the skin

Epigenetic mechanisms and spatial chromatin interactions in the nucleus involving gene promoters and enhancers drive cell differentiation process, while their alterations contribute to the development of many pathological conditions, including inflammation and cancer. Chromatin architectural protein CTCF controls the long-range enhancer/promoter interactions in differentiating cells. To study the role of CTCF in the control of epidermal development, K14-CreER/Ctcf fl/fl mice were generated. K14-driven Ctcf ablation in adult mice resulted in the alterations of epidermal barrier structure followed by massive infiltration of the epidermis by immune cells and development of skin inflammatory response. Microarray analyses of the epidermis of K14-CreER/Ctcf fl/fl mice showed alterations in expression of the genes involved in the control of terminal keratinocyte differentiation, immune response and tumorigenesis. ChIP-seq analyses revealed predominance of the CTCF binding to the distal gene regulatory elements versus gene promoters in epidermal keratinocytes, which supports the CTCF role in the control of enhancer-promoter interactions in keratinocytes. Thus, these data suggest that CTCF plays pivotal roles in the control of epidermal differentiation, skin barrier maintenance and operates as a potent suppressor of the epithelial inflammatory responses in the skin.