Mutant p63 Affects Epidermal Cell Identity through Rewiring the Enhancer Landscape

Jieqiong Qu, Sabine E.J. Tanis, Jos P.H. Smits, Evelyn N. Kouwenhoven, Martin Oti, Ellen H. van den Bogaard, Colin Logie, Hendrik G. Stunnenberg, Hans van Bokhoven, Klaas W. Mulder, Huiqing Zhou

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)


Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Mutations in the p63 DNA-binding domain are associated with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome. However, the underlying molecular mechanism of these mutations remains unclear. Here, we characterized the transcriptome and epigenome of p63 mutant keratinocytes derived from EEC patients. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed an altered enhancer landscape in p63 mutant keratinocytes contributed by loss of p63-bound active enhancers and unexpected gain of enhancers. The gained enhancers were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression and the altered enhancer landscape. Our findings identify a disease mechanism whereby mutant p63 rewires the enhancer landscape and affects epidermal cell identity, consolidating the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes.

Original languageEnglish
Pages (from-to)3490-3503.e4
JournalCell Reports
Issue number12
Publication statusPublished - 18 Dec 2018
Externally publishedYes


  • cell identity
  • EEC syndrome
  • enhancer
  • epidermal keratinocytes
  • p63
  • transcriptional regulation


Dive into the research topics of 'Mutant p63 Affects Epidermal Cell Identity through Rewiring the Enhancer Landscape'. Together they form a unique fingerprint.

Cite this