Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape
Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape
Abstract 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.
Stunnenberg Hendrik G.、Kouwenhoven Evelyn N.、Zhou Huiqing、Qu Jieqiong、Oti Martin、Logie Colin、Tanis Sabine、Smits Jos P.H.、van Bokhoven Hans、van den Bogaard Ellen H.、Mulder Klaas
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud UniversityDepartment of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud UniversityDepartment of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University||Department of Human Genetics, Radboud university medical centerDepartment of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud UniversityDepartment of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud UniversityDepartment of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud UniversityDepartment of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud UniversityDepartment of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud university medical centerDepartment of Human Genetics, Radboud university medical center||Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behavior, Radboud university medical centerDepartment of Dermatology, Radboud Institute for Molecular Life Sciences, Radboud university medical centerDepartment of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University
基础医学分子生物学皮肤病学、性病学
p63enhancercell identitytranscriptional regulationEEC syndrome
Stunnenberg Hendrik G.,Kouwenhoven Evelyn N.,Zhou Huiqing,Qu Jieqiong,Oti Martin,Logie Colin,Tanis Sabine,Smits Jos P.H.,van Bokhoven Hans,van den Bogaard Ellen H.,Mulder Klaas.Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape[EB/OL].(2025-03-28)[2025-04-29].https://www.biorxiv.org/content/10.1101/387902.点此复制
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