Mutant p63 Affects Epidermal Cell Identity Through Rewiring the Enhancer Landscape

Cell Rep. 2018 Dec 18;25(12):3490-3503.e4. doi: 10.1016/j.celrep.2018.11.039.

Abstract

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.

Keywords: EEC syndrome; cell identity; enhancer; epidermal keratinocytes; p63; transcriptional regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Differentiation / genetics
  • Chromatin / metabolism
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Enhancer Elements, Genetic / genetics*
  • Epidermal Cells / cytology*
  • Epidermal Cells / metabolism*
  • Gene Expression Regulation
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Models, Biological
  • Mutation / genetics*
  • Protein Binding
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptome / genetics
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Chromatin
  • Core Binding Factor Alpha 2 Subunit
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins