美国斯坦福大学医学院Joanna Wysocka研究组近日取得一项新成果。他们研究发现人类神经嵴中极远端增强子的丢失导致颅面障碍。2020年9月28日，《细胞-干细胞》发表了这一成果。

SOX9基因周围的大型基因远端的非编码突变会导致人类颅面畸形，这些序列称为Pierre Robin序列（PRS）。利用人类干细胞分化模型，他们确定了在PRS相关区域内的两个增强子簇，这些增强子在面部祖细胞发育限制窗口内调节SOX9表达，距离最远可达1.45 Mb。1.45 Mb簇内的增强子表现出高度的协同活性，这取决于协调基序。使用小鼠模型，他们证明PRS表型特异性源于两种机制的融合：通过环境相关的增强子活性将Sox9剂量扰动限制在发育中的面部结构，以及下颌对Sox9表达降低的敏感性增强。

总体而言，他们表征了参与先天性畸形的最长距离的人类增强子，直接证明了PRS是增强子病，并说明了基因表达的微小变化如何导致形态变异。

附：英文原文

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

Author: 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

Issue&Volume: 2020-09-28

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.

DOI: 10.1016/j.stem.2020.09.001

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30447-1