TY - JOUR T1 - Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape JF - bioRxiv DO - 10.1101/387902 SP - 387902 AU - Jieqiong Qu AU - Sabine Tanis AU - Jos P.H. Smits AU - Evelyn N. Kouwenhoven AU - Martin Oti AU - Ellen H. van den Bogaard AU - Colin Logie AU - Hendrik G. Stunnenberg AU - Hans van Bokhoven AU - Klaas Mulder AU - Huiqing Zhou Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/08/09/387902.abstract N2 - Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. In humans mutations in p63 cause several developmental disorders with defects of ectoderm-derived structures including the epidermis. The underlying molecular mechanisms of these mutations however remain unclear. Here we characterized the transcriptome and epigenome from EEC syndrome patients carrying mutations in the p63 DNA-binding domain. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed that the deregulated gene expression in p63 mutant keratinocytes resulted from an altered enhancer landscape contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers in mutant keratinocytes were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression as well as the enhancer distribution. Our findings support the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes and identify a novel mechanism whereby p63 DNA-binding mutations associated with EEC syndrome rewire the enhancer landscape and affect epidermal cell identity. ER -