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 Visel; Licia Selleri; Joanna Wysocka

doi:10.1016/j.stem.2020.09.001

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

Deanery of Molecular, Genetic and Population Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 language	English
Pages (from-to)	765-783.e14
Journal	Cell Stem Cell
Volume	27
Issue number	5
DOIs	https://doi.org/10.1016/j.stem.2020.09.001
Publication status	Published - 5 Nov 2020

Keywords / Materials (for Non-textual outputs)

Cell Differentiation
Humans
Mutation/genetics
Neural Crest
Pierre Robin Syndrome
Regulatory Sequences, Nucleic Acid
SOX9 Transcription Factor/genetics

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10.1016/j.stem.2020.09.001Licence: Creative Commons: Attribution (CC-BY)

Loss of Extreme Long-Range Enhancers in HumanFinal published version, 4.15 MBLicence: CC BY

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Long, H. K., Osterwalder, M., Welsh, I. C., Hansen, K., Davies, J. O. J., Liu, Y. E., Koska, M., Adams, A. T., Aho, R., Arora, N., Ikeda, K., Williams, R. M., Sauka-Spengler, T., Porteus, M. H., Mohun, T., Dickel, D. E., Swigut, T., Hughes, J. R., Higgs, D. R., ... Wysocka, J. (2020). Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder. Cell Stem Cell, 27(5), 765-783.e14. https://doi.org/10.1016/j.stem.2020.09.001

@article{b573d5e5548f405e90c505f530b2b900,

title = "Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder",

abstract = "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.",

keywords = "Cell Differentiation, Humans, Mutation/genetics, Neural Crest, Pierre Robin Syndrome, Regulatory Sequences, Nucleic Acid, SOX9 Transcription Factor/genetics",

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

year = "2020",

month = nov,

day = "5",

doi = "10.1016/j.stem.2020.09.001",

language = "English",

volume = "27",

pages = "765--783.e14",

journal = "Cell Stem Cell",

issn = "1934-5909",

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number = "5",

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Long, HK, Osterwalder, M, Welsh, IC, Hansen, K, Davies, JOJ, Liu, YE, Koska, M, Adams, AT, Aho, R, Arora, N, Ikeda, K, Williams, RM, Sauka-Spengler, T, Porteus, MH, Mohun, T, Dickel, DE, Swigut, T, Hughes, JR, Higgs, DR, Visel, A, Selleri, L & Wysocka, J 2020, 'Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder', Cell Stem Cell, vol. 27, no. 5, pp. 765-783.e14. https://doi.org/10.1016/j.stem.2020.09.001

TY - JOUR

T1 - Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder

AU - Long, Hannah K

AU - Osterwalder, Marco

AU - Welsh, Ian C

AU - Hansen, Karissa

AU - Davies, James O J

AU - Liu, Yiran E

AU - Koska, Mervenaz

AU - Adams, Alexander T

AU - Aho, Robert

AU - Arora, Neha

AU - Ikeda, Kazuya

AU - Williams, Ruth M

AU - Sauka-Spengler, Tatjana

AU - Porteus, Matthew H

AU - Mohun, Tim

AU - Dickel, Diane E

AU - Swigut, Tomek

AU - Hughes, Jim R

AU - Higgs, Douglas R

AU - Visel, Axel

AU - Selleri, Licia

AU - Wysocka, Joanna

PY - 2020/11/5

Y1 - 2020/11/5

N2 - 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.

AB - 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.

KW - Cell Differentiation

KW - Humans

KW - Mutation/genetics

KW - Neural Crest

KW - Pierre Robin Syndrome

KW - Regulatory Sequences, Nucleic Acid

KW - SOX9 Transcription Factor/genetics

U2 - 10.1016/j.stem.2020.09.001

DO - 10.1016/j.stem.2020.09.001

M3 - Article

C2 - 32991838

SN - 1934-5909

VL - 27

SP - 765-783.e14

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 5

ER -

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

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Keywords / Materials (for Non-textual outputs)

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