Auricular malformations are driven by copy number variations in a hierarchical enhancer cluster and a dominant enhancer recapitulates human pathogenesis
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.
Authors
- Xiaoying Fan (ORCID: https://orcid.org/0000-0002-5497-6178)
- Jintian Hu (ORCID: https://orcid.org/0000-0003-2036-2343)
- Qingpei Huang (ORCID: https://orcid.org/0000-0002-3379-237X)
- Jia Liu (ORCID: https://orcid.org/0000-0002-5684-9594)
- Yong‐Biao Zhang (ORCID: https://orcid.org/0000-0002-2764-2148)
- Bingqing Wang (ORCID: https://orcid.org/0000-0002-3803-8413)
- Timothy C. Cox (ORCID: https://orcid.org/0000-0001-8015-5528)
- Zhiying Liao (ORCID: https://orcid.org/0000-0003-4314-9238)
- Stylianos E. Antonarakis (ORCID: https://orcid.org/0000-0001-8907-5823)
- Baichuan Xiao (ORCID: https://orcid.org/0000-0001-7608-8043)
- Wenxin Xu (ORCID: https://orcid.org/0009-0008-0813-5969)
- Jiao Zhang (ORCID: https://orcid.org/0000-0002-9456-3992)
- Qi Chen (ORCID: https://orcid.org/0000-0001-6353-9589)
- Jiaqiang Wang (ORCID: https://orcid.org/0000-0003-0202-2046)
- Qiang Li (ORCID: https://orcid.org/0000-0003-1119-8692)
- Hao‐Jie Zhu (ORCID: https://orcid.org/0000-0002-2248-4419)
- Huisheng Liu (ORCID: https://orcid.org/0000-0001-5371-7943)
- Ziqiu Meng
- Jian Huang (ORCID: https://orcid.org/0009-0001-5085-8422)
- R. E. Lang
- X. Tang
- Xi Han
- Qingguo Zhang
- Xiaopeng Xu
- Jiqiang Liu (ORCID: https://orcid.org/0009-0000-5576-9587)
Institutions
- University of Geneva (CH)
- University of Science and Technology of China (CN)
- Shandong University of Traditional Chinese Medicine (CN)
- Army Medical University (CN)
- Xuzhou Medical College (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Guangzhou Experimental Station (CN)
- Daping Hospital (CN)
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (CN)
- Guangzhou Chemistry (China) (CN)
- University of Missouri–Kansas City (US)
- Beihang University (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-17
- DOI
- https://doi.org/10.1038/s41467-025-59735-w
- Citations
- 1
- Primary Topic
- Tumors and Oncological Cases
- Type
- article
- Field-Weighted Citation Impact
- 1.47
Funders
- Westlake University
- National Natural Science Foundation of China
- Sun Yat-sen University
- China Postdoctoral Science Foundation
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- Bijzonder Onderzoeksfonds UGent