Science2013-10-25 10:27 PM

Fine Tuning of Craniofacial Morphology by Distant-Acting Enhancers 远程增强子对颅面形态的微调

Abstract Introduction The shape of the face is one of the most distinctive features among humans, and differences in facial morphology have substantial implications in areas such as social interaction, psychology, forensics, and clinical genetics. Craniofacial shape is highly heritable, including the normal spectrum of morphological variation as well as susceptibility to major craniofacial birth defects. In this study, we explored the role of transcriptional enhancers in the development of the craniofacial complex. Our study is based on the rationale that such enhancers, which can be hundreds of kilobases away from their target genes, regulate the spatial patterns, levels, and timing of gene expression in normal development. 简介 脸型的差异是区别人与人之间的最与众不同的特色之一,面部形态的差异显著影响了社会交往,心理学,法医,临床遗传学等各个领域。颅面形状具有高度遗传性,包括正常形态学变化的图谱以及对主要颅面先天畸形的敏感性。在这项研究中,我们探索了转录增强子在颅面复合体发展中所扮演的角色。这类增强子远离靶基因成百千碱基对之外,能够在正常发展中调节基因表达的空间模式,级别和时机,我们的研究就基于这样的基本原理之上。 Methods To identify distant-acting enhancers active during craniofacial development, we used chromatin immunoprecipitation on embryonic mouse face tissue followed by sequencing to identify noncoding genome regions bound by the enhancer-associated p300 protein. We used LacZ reporter assays in transgenic mice and optical projection tomography (OPT) to determine three-dimensional expression patterns of a subset of these candidate enhancers. Last, we deleted three of the craniofacial enhancers from the mouse genome to assess their effect on gene expression and craniofacial morphology during development. 方法 为了确定在颅面发展中起远程影响作用的增强子的活跃性,我们按测序在胚胎小鼠面部组织使用了染色质免疫沉淀技术来确定由与增强子相关的p300蛋白限制的非编码基因组区域。我们使用有关转基因小鼠和光学投影层析成像(OPT)的LacZ报告测定来确定这些候选增强子其中一子集的三维表达模式。最后我们删除了来自于小鼠基因组里的颅面增强子中的其中三个来评估他们在基因表达和发展过程中对颅面形态的影响。 Results We identified more than 4000 candidate enhancer sequences predicted to be active in the developing craniofacial complex. The majority of these sequences are at least partially conserved between humans and mice, and many are located in chromosomal regions associated with normal facial morphology or craniofacial birth defects. Characterization of more than 200 candidate enhancer sequences in transgenic mice revealed a remarkable spatial complexity of in vivo expression patterns. Targeted deletions of three craniofacial enhancers near genes with known roles in craniofacial development resulted in changes of expression of those genes as well as quantitatively subtle but definable alterations of craniofacial shape. 结果 我们确定了四千多个候选增强子序列,预计这些序列将活跃影响颅面复合物的发展。这些序列中的绝大部分至少部分保存于人类和小鼠之间,其中许多位于与正常面部形态或颅面先天畸形相关的染色体区域中。在转基因小鼠中的两百多个候选增强子序列的特性,通过在体表达模式,揭示了显著的空间复杂度。对基因附近三种已知影响颅面发展的颅面增强子的目标删除影响了这些基因的表达和颅面形态方面数量上微妙但可确定的改变。 Discussion Our analysis identifies enhancers that fine tune expression of genes during craniofacial development in mice. These results support that variation in the sequence or copy number of craniofacial enhancers may contribute to the spectrum of facial variation we find in human populations. Because many craniofacial enhancers are located in genome regions associated with craniofacial birth defects, such as clefts of the lip and palate, our results also offer a starting point for exploring the contribution of noncoding sequences to these disorders. 讨论 我们的分析确定了那些在小鼠颅面发展中能很好调整基因表达的增强子。这些结果证实了颅面增强子序列或数量复制的变化可能有助于描绘已发现人口中面部差异的图谱。因为位于基因组区域的许多颅面增强子与颅面先天畸形有关,比如唇腭裂,我们的研究还给探索关于非编码序列对这些疾病的贡献提供了一个起点。

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