Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Am J Hum Genet. 2012 Sep 7;91(3):435-43. doi: 10.1016/j.ajhg.2012.07.007. Epub 2012 Aug 23.
The basis for impaired differentiation in TP63 mutant ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome is unknown. Human epidermis harboring AEC TP63 mutants recapitulated this impairment, along with downregulation of differentiation activators, including HOPX, GRHL3, KLF4, PRDM1, and ZNF750. Gene-set enrichment analysis indicated that disrupted expression of epidermal differentiation programs under the control of ZNF750 and KLF4 accounted for the majority of disrupted epidermal differentiation resulting from AEC mutant TP63. Chromatin immunoprecipitation (ChIP) analysis and ChIP-sequencing of TP63 binding in differentiated keratinocytes revealed ZNF750 as a direct target of wild-type and AEC mutant TP63. Restoring ZNF750 to AEC model tissue rescued activator expression and differentiation, indicating that AEC TP63-mediated ZNF750 inhibition contributes to differentiation defects in AEC. Incorporating disease-causing mutants into regenerated human tissue can thus dissect pathomechanisms and identify targets that reverse disease features.
TP63 突变型先天性并指-外胚层发育不全-唇腭裂（AEC）综合征中分化障碍的基础尚不清楚。携带 AEC TP63 突变的人表皮重现了这种损伤，同时分化激活物（包括 HOPX、GRHL3、KLF4、PRDM1 和 ZNF750）的下调。基因集富集分析表明，ZNF750 和 KLF4 控制的表皮分化程序的表达中断，导致 AEC 突变型 TP63 引起的大多数表皮分化中断。分化角质形成细胞中 TP63 结合的染色质免疫沉淀（ChIP）分析和 ChIP-seq 显示 ZNF750 是野生型和 AEC 突变型 TP63 的直接靶标。将 ZNF750 恢复到 AEC 模型组织中可挽救激活剂的表达和分化，表明 AEC TP63 介导的 ZNF750 抑制导致 AEC 中的分化缺陷。将致病突变体纳入再生的人类组织中，因此可以剖析发病机制并确定可逆转疾病特征的靶标。
