SCIENCE@home

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,T. 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,S. Antonarakis,Jiao Zhang,Xiaoying Fan,Huisheng Liu,Yongbiao Zhang

Published 2025 in Nature Communications

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. Here, the authors identify a copy number variation containing three enhancers (PIHEC) that drives bilateral constricted ear by co-ordinately regulating HMX1 expression, revealing how aberrant Hmx1 expression in neural crest-derived fibroblasts disrupts outer ear development.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-88 of 88 references · Page 1 of 1

CITED BY