Long-range enhancers regulating Myc expression are required for normal facial morphogenesis
Long-range enhancers regulating Myc expression are required for normal facial morphogenesis
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DOI：
10.1038/ng.2971
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发表时间：
2014-07-01
期刊：
影响因子：
30.8
通讯作者：
Spitz, Francois
中科院分区：
文献类型：
--
作者：
Uslu, Veil Vural;Petretich, Massimo;Spitz, Francois
唇裂伴或不伴腭裂（CL/P）是人类最常见的先天性畸形之一，每500- 1，000例新生儿中发生1例（1，2）。8 q24处的640 kb非编码区间与人类非综合征性CL/P风险增加相关（3-5），但参与这种遗传易感性的基因和途径仍然难以捉摸。使用一个大系列的重排设计的同线小鼠区域，我们表明，这个间隔包含非常遥远的顺式作用增强子，控制Myc表达在发展中的脸。缺失该间隔导致小鼠面部形态的轻度改变，偶尔导致CUP。在分子水平上，我们确定了几个下游基因的错误表达，突出了颅面发育网络和细胞的一般代谢能力对未来上唇的综合影响。这种双重分子病因学可以解释8 q24区域的变异对人类面部畸形的显著影响。
Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations observed in humans, with 1 occurrence in every 500-1,000 births(1,2). A 640-kb noncoding interval at 8q24 has been associated with increased risk of non-syndromic CL/P in humans(3-5), but the genes and pathways involved in this genetic susceptibility have remained elusive. Using a large series of rearrangements engineered over the syntenic mouse region, we show that this interval contains very remote cis-acting enhancers that control Myc expression in the developing face. Deletion of this interval leads to mild alteration of facial morphology in mice and, sporadically, to CUP. At the molecular level, we identify misexpression of several downstream genes, highlighting combined impact on the craniofacial developmental network and the general metabolic capacity of cells contributing to the future upper lip. This dual molecular etiology may account for the prominent influence of variants in the 8q24 region on human facial dysmorphologies.