Mutant p63 Affects Epidermal Cell Identity through Rewiring the Enhancer Landscape

• DOI: 10.1016/j.celrep.2018.11.039
• Publication Date: 2018-12-18T10:39:17Z
• Authors: Jieqiong Qu; Sabine E.J. Tanis; Jos P.H. Smits; Evelyn N. Kouwenh...; Martin Oti; Ellen H. van den ...; Colin Logie; Hendrik G. Stunne...; Hans van Bokhoven; Klaas W. Mulder; Huiqing Zhou
• Keywords: Keratinocytes; 0301 basic medicine; Transcription, Genetic; QH301-705.5; Dermatology - Radboud University Medical Center; Models, Biological; 03 medical and health sciences; Humans; Cognitive Neuroscience - Radboud University Medical Center; Amino Acid Sequence; Radboudumc 5: Inflammatory diseases RIMLS: Radboud Institute for Molecular Life Sciences; Biology (General); Molecular Biology; Radboudumc 10: Reconstructive and regenerative medicine RIMLS: Radboud Institute for Molecular Life Sciences; 0303 health sciences; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Tumor Suppressor Proteins; Cell Differentiation; Chromatin; Enhancer Elements, Genetic; Epidermal Cells; Gene Expression Regulation; Core Binding Factor Alpha 2 Subunit; Mutation; Molecular Developmental Biology; Transcriptome; Protein Binding; Transcription Factors

AbstractTranscription 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.