Enhancer-adoption as a mechanism of human developmental disease
Enhancer-adoption as a mechanism of human developmental disease
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DOI：
10.1002/humu.21615
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发表时间：
2011-12-01
期刊：
影响因子：
3.9
通讯作者：
FitzPatrick, David R.
中科院分区：
文献类型：
--
作者：
Lettice, Laura A.;Daniels, Sarah;FitzPatrick, David R.
发育基因表达的长程顺式调控的破坏越来越被认为是人类疾病的原因。在这里，我们报告了一种新型的长程顺式调节突变，其中基因的异位表达是由不属于其自身的增强子驱动的。我们将这种监管信息的获得称为增强剂采用。我们绘制了一名患有前脑无裂谱系 (HPES) 疾病和严重上肢并指合并下肢并指的儿童的从头 7q 倒转的断点。 HPES 似乎是由 7q36.3 断点导致的，该断点使音刺猬 (SHH) 基因与已知驱动早期前脑表达的增强子脱位。然而，肢体表型不能用已知 SHH 增强子的缺失来解释。 SHH 转录单元重新定位到 7q22.1，类似于 EMID2 内含子内高度保守的非编码元件 (HCNE2) 的 190 kb 3'。我们发现 HCNE2 在小鼠胚胎中充当肢芽增强子，并在体内驱动 Shh 的异位表达，重现儿童的肢表型。这种发育遗传机制可以解释与平衡染色体重排相关的一部分新的或无法解释的表型。 32:14921499, 2011。(C) 2011 Wiley 期刊公司。
Disruption of the long-range cis-regulation of developmental gene expression is increasingly recognized as a cause of human disease. Here, we report a novel type of long-range cis-regulatory mutation, in which ectopic expression of a gene is driven by an enhancer that is not its own. We have termed this gain of regulatory information as enhancer adoption. We mapped the breakpoints of a de novo 7q inversion in a child with features of a holoprosencephaly spectrum (HPES) disorder and severe upper limb syndactyly with lower limb synpolydactyly. The HPES plausibly results from the 7q36.3 breakpoint dislocating the sonic hedgehog (SHH) gene from enhancers that are known to drive expression in the early forebrain. However, the limb phenotype cannot be explained by loss of known SHH enhancers. The SHH transcription unit is relocated to 7q22.1, similar to 190 kb 3' of a highly conserved noncoding element (HCNE2) within an intron of EMID2. We show that HCNE2 functions as a limb bud enhancer in mouse embryos and drives ectopic expression of Shh in vivo recapitulating the limb phenotype in the child. This developmental genetic mechanism may explain a proportion of the novel or unexplained phenotypes associated with balanced chromosome rearrangements. 32:14921499, 2011. (C) 2011 Wiley Periodicals, Inc.