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

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Loss of Extreme Long-Range Enhancers in Human Neural Crest Drives a Craniofacial Disorder
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-09-28 , DOI: 10.1016/j.stem.2020.09.001
Hannah K Long ₁ , Marco Osterwalder ₂ , Ian C Welsh ₃ , Karissa Hansen ₃ , James O J Davies ₄ , Yiran E Liu ₅ , Mervenaz Koska ₆ , Alexander T Adams ₇ , Robert Aho ₃ , Neha Arora ₈ , Kazuya Ikeda ₉ , Ruth M Williams ₁₀ , Tatjana Sauka-Spengler ₁₀ , Matthew H Porteus ₉ , Tim Mohun ₁₁ , Diane E Dickel ₂ , Tomek Swigut ₈ , Jim R Hughes ₄ , Douglas R Higgs ₁₂ , Axel Visel ₁₃ , Licia Selleri ₃ , Joanna Wysocka ₁₄

Affiliation

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
Program in Craniofacial Biology, Department of Orofacial Sciences and Department of Anatomy, Institute of Human Genetics, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway, Mill Hill, London NW7 1AA, UK.
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; Laboratory of Gene Regulation, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; School of Natural Sciences, University of California, Merced, Merced, CA 95343, USA.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.

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.

中文翻译：

人类神经嵴中极端长程增强剂的缺失导致颅面疾病

SOX9基因周围大型基因荒漠远端的非编码突变会导致一种称为皮埃尔·罗宾序列 (PRS) 的人类颅面疾病。利用人类干细胞分化模型，我们在 PRS 相关区域内鉴定了两簇增强子，它们在面部祖细胞发育的受限窗口期间调节SOX9 的表达，距离可达 1.45 Mb。 1.45 Mb 簇内的增强子表现出依赖于协调子基序的高度协同活性。使用小鼠模型，我们证明 PRS 表型特异性源于两种机制的融合：通过特定环境的增强子活性将Sox9剂量扰动限制到正在发育的面部结构，以及提高下颌对Sox9表达减少的敏感性。总体而言，我们描述了与先天性畸形有关的最长范围的人类增强子，直接证明 PRS 是一种增强子病，并说明基因表达的微小变化如何导致形态变异。

更新日期：2020-11-06

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