Auricular malformations are driven by copy number variations in a hierarchical enhancer cluster and a dominant enhancer recapitulates human pathogenesis

Xiaopeng Xu, Qi Chen, Qingpei Huang, Timothy C. Cox, Hao Zhu, Jintian Hu, Xi Han, Ziqiu Meng, Bingqing Wang, Zhiying Liao, Wenxin Xu, Baichuan Xiao, Ruirui Lang, Jiqiang Liu, Jian Huang, Xiaokai Tang, Jinmo Wang, Qiang Li, Ting Liu, Qingguo Zhang, Stylianos E. Antonarakis, Jiao Zhang (), Xiaoying Fan (), Huisheng Liu () and Yong-Biao Zhang ()
Additional contact information
Xiaopeng Xu: Guangzhou National Laboratory
Qi Chen: Chinese Academy of Medical Sciences
Qingpei Huang: Guangzhou National Laboratory
Timothy C. Cox: University of Missouri-Kansas City
Hao Zhu: Beihang University
Jintian Hu: Chinese Academy of Medical Sciences
Xi Han: Guangzhou National Laboratory
Ziqiu Meng: Beihang University
Bingqing Wang: Chinese Academy of Medical Sciences
Zhiying Liao: Guangzhou National Laboratory
Wenxin Xu: Guangzhou National Laboratory
Baichuan Xiao: Beihang University
Ruirui Lang: Beihang University
Jiqiang Liu: Beihang University
Jian Huang: Beihang University
Xiaokai Tang: Beihang University
Jinmo Wang: Beihang University
Qiang Li: Affiliated Hospital of Xuzhou Medical University
Ting Liu: Army Medical University
Qingguo Zhang: Chinese Academy of Medical Sciences
Stylianos E. Antonarakis: University of Geneva Medical Faculty
Jiao Zhang: Shandong collaborative innovation research institute of traditional Chinese medicine industry
Xiaoying Fan: Guangzhou National Laboratory
Huisheng Liu: Guangzhou National Laboratory
Yong-Biao Zhang: Beihang University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Enhancers, through the combinatorial action of transcription factors (TFs), dictate both the spatial specificity and the levels of gene expression, and their aberrations can result in diseases. While a HMX1 downstream enhancer is associated with ear malformations, the mechanisms underlying bilateral constricted ear (BCE) remain unclear. Here, we identify a copy number variation (CNV) containing three enhancers—collectively termed the positional identity hierarchical enhancer cluster (PI-HEC)—that drives BCE by coordinately regulating HMX1 expression. Each enhancer exhibits distinct activity-location-structure features, and the dominant enhancer with high mobility group (HMG)-box combined with Coordinator and homeodomain TF motifs modulating its activity and specificity, respectively. Mouse models demonstrate that neural crest-derived fibroblasts with aberrant Hmx1 expression in the basal pinna, along with ectopic distal pinna expression, disrupt outer ear development, affecting cartilage, muscle, and epidermis. Our findings elucidate mammalian ear morphogenesis and underscore the complexity of synergistic regulation among enhancers and between enhancers and transcription factors.

Date: 2025
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DOI: 10.1038/s41467-025-59735-w

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