biostudies-literatureDeelen LUKRI | Biotechnology and Biological Sciences Research CouncilWellcome TrustBiotechnology and Biological Sciences Research Council1731-1747https://www.ebi.ac.uk/biostudies/studies/S-EPMC12673149biostudies-literatureUnknown21(12)Craniofacial development is evolutionarily conserved, yet subtle changes in its regulatory network drive species-specific traits. Transposable elements (TEs) contribute to genome evolution, but their role in cranial neural crest cells (CNCCs) remains unclear. Here, we investigate the domestication of hominoid-specific TEs (LTR5Hs and SVAs) as enhancers during human CNCC specification, a process critical for vertebrate craniofacial development. Using human iPSC-derived CNCCs, we identified ~515 hominoid-specific TEs functioning as enhancers, including ~250 human-specific, predominantly LTR5Hs. These elements are enriched for CNCC coordinator motifs, are bound by the CNCC signature factor TWIST1, and their enhancer activity appears largely CNCC-specific. CRISPR-interference targeting ~75% ofMolecular systems biologyHominoid-specific transposable elements reshaped neural crest migration in craniofacial development.PMC12673149BB/Y000854/1104931/Z/14/ZBB/L015129/1Mitchell ZHKoulle ADemurtas MGarcia Del Valle BTrizzino MDeelen LfalseHominoid-specific transposable elements reshaped neural crest migration in craniofacial development.Craniofacial development is evolutionarily conserved, yet subtle changes in its regulatory network drive species-specific traits. Transposable elements (TEs) contribute to genome evolution, but their role in cranial neural crest cells (CNCCs) remains unclear. Here, we investigate the domestication of hominoid-specific TEs (LTR5Hs and SVAs) as enhancers during human CNCC specification, a process critical for vertebrate craniofacial development. Using human iPSC-derived CNCCs, we identified ~515 hominoid-specific TEs functioning as enhancers, including ~250 human-specific, predominantly LTR5Hs. These elements are enriched for CNCC coordinator motifs, are bound by the CNCC signature factor TWIST1, and their enhancer activity appears largely CNCC-specific. CRISPR-interference targeting ~75% of2025-01-01T00:00:00Z2025 Dec2026-06-05T22:20:32.608Z2026-05-22T03:16:10.247ZS-EPMC126731494098365610.1038/s44320-025-00151-z