Human-specific transposable elements shaped the evolution of craniofacial development through regulation of neural crest migration

ABSTRACT: Craniofacial development and neural crest specification are evolutionarily conserved processes, yet subtle modifications to their gene regulatory networks drive species-specific craniofacial diversity. Transposable elements (TEs) are increasingly recognized as contributors to genome evolution, but their role in shaping neural crest regulatory programs remains underexplored. Here, we investigate the domestication of hominoid-specific TEs as enhancers during cranial neural crest cell (CNCC) specification, a process critical for vertebrate head development. Using human iPSC-derived CNCCs, we identified ~250 human-specific TEs, half of which human-specific, acting as active enhancers. These TEs were predominantly LTR5Hs and, to a lesser extent, SVAs. We demonstrate that these elements have been co-opted through the acquisition of a conserved CNCC coordinator motif and are bound by the CNCC signature factor TWIST1, and that their co-option is largely specific to the CNCC cell type. To assess their functional relevance, we used CRISPR-interference to repress ~75% of all the LTR5Hs and SVAs active in CNCCs, leading to widespread transcriptional changes in genes associated with neural crest migration, a process essential for CNCCs to populate the embryo and form craniofacial structures. Using functional assays, we showed that CNCC migration was significantly impaired by CRISPR-mediated TE repression. We further demonstrated that genes near human-specific TEs are more highly expressed in human CNCCs relative to chimpanzee, but TE repression returns their expression to chimpanzee levels. These findings reveal how TEs have been repeatedly co-opted to fine-tune CNCC regulatory networks, shaping lineage-specific craniofacial traits. By integrating evolutionary and developmental perspectives, our study highlights how TEs contribute to regulatory innovations in an otherwise deeply conserved developmental program.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292478 | GEO | 2025/03/23

REPOSITORIES: GEO