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

Author

Listed:
  • Xiaopeng Xu

    (Guangzhou National Laboratory
    Beihang University
    Bioland 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
    University of Science and Technology of China (USTC))

  • 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
    Swiss Institute of Genomic Medicine
    iGE3 Institute of Genetics and Genomes in Geneva)

  • Jiao Zhang

    (Shandong collaborative innovation research institute of traditional Chinese medicine industry)

  • Xiaoying Fan

    (Guangzhou National Laboratory
    Bioland Laboratory
    The Fifth Affiliated Hospital of Guangzhou Medical University
    GMU-GIBH Joint School of Life Sciences)

  • Huisheng Liu

    (Guangzhou National Laboratory
    Bioland Laboratory
    Guangzhou Medical University)

  • Yong-Biao Zhang

    (Beihang University
    Ministry of Industry and Information Technology)

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.

Suggested Citation

  • 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 , 2025. "Auricular malformations are driven by copy number variations in a hierarchical enhancer cluster and a dominant enhancer recapitulates human pathogenesis," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59735-w
    DOI: 10.1038/s41467-025-59735-w
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