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| Status |
Public on Mar 31, 2025 |
| Title |
Auricular Malformations Driven by Copy Number Variations in a Hierarchical Enhancer Cluster and Dominant Enhancer Recapitulates Human Pathogenesis |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 HMX1 downstream enhancer is associated to 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 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.
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| Overall design |
Using of scRNA-seq compare transcriptional difference bewteen wild type and mEC1 knock-in transgenic mouse models.
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| Contributor(s) |
Xu X, Chen Q, Huang Q, C. Cox T, Zhu H, Hu J, Han X, Meng Z, Wang B, Liao Z, Xu W, Xiao B, Lang R, Liu J, Huang J, Tang X, Wang J, Li Q, Liu T, Zhang Q, E. Antonarakis S, Zhang J, Fan X, Liu H, Zhang Y |
| Citation missing |
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| Submission date |
Mar 31, 2025 |
| Last update date |
Apr 01, 2025 |
| Contact name |
Xu Xiaopeng |
| E-mail(s) |
xu_xiaopeng@gzlab.ac.cn
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| Organization name |
Guangzhou National Laboratory
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| Street address |
96 Xingdao South Road, Guangzhou International Bio Island, Haizhu District
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| City |
Guangzhou |
| ZIP/Postal code |
510320 |
| Country |
China |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (2) |
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| Relations |
| BioProject |
PRJNA1244370 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE293403_RAW.tar |
434.9 Mb |
(http)(custom) |
TAR (of TAR) |
SRA Run Selector |
| Raw data are available in SRA |
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