Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder

Hannah K. Long, Marco Osterwalder, Ian C. Welsh, Karissa Hansen, James O.J. Davies, Yiran E. Liu, Mervenaz Koska, Alexander T. Adams, Robert Aho, Neha Arora, Kazuya Ikeda, Ruth M. Williams, Tatjana Sauka-Spengler, Matthew H. Porteus, Tim Mohun, Diane E. Dickel, Tomek Swigut, Jim R. Hughes, Douglas R. Higgs, Axel ViselLicia Selleri, Joanna Wysocka

Research output: Contribution to journalArticlepeer-review


Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). Leveraging a human stem cell differentiation model, we identify two clusters of enhancers within the PRS-associated region that regulate SOX9 expression during a restricted window of facial progenitor development at distances up to 1.45 Mb. Enhancers within the 1.45 Mb cluster exhibit highly synergistic activity that is dependent on the Coordinator motif. Using mouse models, we demonstrate that PRS phenotypic specificity arises from the convergence of two mechanisms: confinement of Sox9 dosage perturbation to developing facial structures through context-specific enhancer activity and heightened sensitivity of the lower jaw to Sox9 expression reduction. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and illustrate how small changes in gene expression can lead to morphological variation.

Original languageEnglish
Pages (from-to)765-783.e14
Number of pages34
JournalCell Stem Cell
Issue number5
Early online date28 Sept 2020
Publication statusPublished - 5 Nov 2020


  • craniofacial
  • enhancer
  • enhanceropathy
  • gene dosage
  • long-range regulation
  • neural crest
  • non-coding mutation
  • Pierre Robin sequence
  • SOX9
  • transcription


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