p63 establishes epithelial enhancers at critical craniofacial development genes
p63 establishes epithelial enhancers at critical craniofacial development genes
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DOI：
10.1126/sciadv.aaw0946
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发表时间：
2019-05-01
期刊：
影响因子：
13.6
通讯作者：
Berger, Shelley L.
中科院分区：
文献类型：
--
作者：
Lin-Shiao, Enrique;Lan, Yemin;Berger, Shelley L.
转录因子p63是表皮发育的关键介质。患者p63的点突变导致发育缺陷，包括口面裂。迄今为止，关于p63在人类颅面发育中的关键作用的知识是有限的。使用诱导型转分化模型，结合表观基因组测序和全基因组关联研究数据的多队列荟萃分析，我们发现p63在颅面发育基因中建立增强子来调节其转录。p63的DNA结合结构域或无菌α基序蛋白相互作用结构域中的疾病特异性取代突变分别消除或减少这些增强子的建立。我们发现，由p63建立的增强子高度富集与非综合征性唇裂+/-腭裂（CL/P）相关的单核苷酸多态性。这些正交方法表明p63增强子功能和CL/P之间有很强的分子联系，阐明了这种发育缺陷的分子机制，并揭示了重要的调控元件和新的候选致病基因。
The transcription factor p63 is a key mediator of epidermal development. Point mutations in p63 in patients lead to developmental defects, including orofacial clefting. To date, knowledge on how pivotal the role of p63 is in human craniofacial development is limited. Using an inducible transdifferentiation model, combined with epigenomic sequencing and multicohort meta-analysis of genome-wide association studies data, we show that p63 establishes enhancers at craniofacial development genes to modulate their transcription. Disease-specific substitution mutation in the DNA binding domain or sterile alpha motif protein interaction domain of p63, respectively, eliminates or reduces establishment of these enhancers. We show that enhancers established by p63 are highly enriched for single-nucleotide polymorphisms associated with nonsyndromic cleft lip +/- cleft palate (CL/P). These orthogonal approaches indicate a strong molecular link between p63 enhancer function and CL/P, illuminating molecular mechanisms underlying this developmental defect and revealing vital regulatory elements and new candidate causative genes.