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Mutant p63 Affects Epidermal Cell Identity through Rewiring the Enhancer Landscape
Jieqiong Qu1, Sabine E J Tanis1, Jos P H Smits2
1Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
Cell Reports
|December 20, 2018
Summary
Mutant p63 disrupts epidermal cell identity by altering gene regulation and enhancer landscape. This rewiring, involving transcription factor RUNX1, offers insights into ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Transcription factor p63 is crucial for skin development and function.
- Mutations in p63 cause EEC syndrome, but the molecular basis is unknown.
Purpose of the Study:
- To investigate the molecular mechanisms underlying p63 mutations in EEC syndrome.
- To characterize the transcriptome and epigenome of p63 mutant keratinocytes.
Main Methods:
- Transcriptome sequencing of patient-derived keratinocytes.
- Epigenomic profiling to analyze enhancer activity.
- Functional studies involving transcription factor manipulation (RUNX1).
Main Results:
- p63 mutant keratinocytes exhibit altered gene expression, deviating from normal epidermal identity.
- Epigenomic analysis reveals significant changes in the enhancer landscape, including loss and gain of active enhancers.
- Overexpression of RUNX1 was observed in gained enhancers, and its reduction partially restored normal gene expression and enhancer activity.
Conclusions:
- Mutant p63 rewires the enhancer landscape, leading to altered epidermal cell identity.
- RUNX1 is implicated in the aberrant enhancer activity associated with p63 mutations.
- This study elucidates a disease mechanism for EEC syndrome involving p63's role in controlling the epidermal epigenome.
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