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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 publication

DOI

10.1016/j.stem.2020.09.001

Type

Journal article

Journal

Cell Stem Cell

Publication Date

05/11/2020

Volume

27

Pages

765 - 783.e14

Keywords

Pierre Robin sequence, SOX9, craniofacial, enhancer, enhanceropathy, gene dosage, long-range regulation, neural crest, non-coding mutation, transcription, Cell Differentiation, Humans, Mutation, Neural Crest, Pierre Robin Syndrome, Regulatory Sequences, Nucleic Acid, SOX9 Transcription Factor