Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

Author:

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

Abstract

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.

Publisher

Cold Spring Harbor Laboratory

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3