A novel long-range enhancer regulates postnatal expression of Zeb2: implications for Mowat-Wilson syndrome phenotypes
A novel long-range enhancer regulates postnatal expression of Zeb2: implications for Mowat-Wilson syndrome phenotypes
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DOI：
10.1093/hmg/dds389
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发表时间：
2012-12-15
影响因子：
3.5
通讯作者：
Carter, David A.
中科院分区：
文献类型：
--
作者：
El-Kasti, Muna M.;Wells, Timothy;Carter, David A.
锌指 E 盒结合同源框 2 (Zeb2) 基因编码 SMAD 相互作用转录因子，在发育和疾病中发挥多种作用。 hZeb2 位点突变会导致 MowatWilson 综合征 (MWS)，这是一种与智力低下和其他病例和性别相关的临床特征相关的遗传性疾病。最近的研究详细介绍了 microRNA 介导的 Zeb2 控制，但对该基因的基因组背景或可能指导其多种功能的增强子序列知之甚少。在这里，我们描述了一种新型转基因啮齿动物模型，其中 Zeb2 调控序列被破坏，导致产后发育表型为常染色体显性遗传。该表型表现出基因型与性别的相互作用，主要表现为男性出生后肾脏发育的急剧减弱。胚胎和新生儿发育的其他方面，包括神经元，不受影响。转基因插入位点与 Zeb2 上游 1.2 Mb 的 12 kb 缺失相关，位于 4.1 Mb 基因荒漠内。来自删除区域的保守序列增强了转录测定中的 Zeb2 启动子活性。该增强子活性的组织和时间限制可能涉及结合该序列的蛋白质的出生后变化。对照人/小鼠 VISTA 增强子（Zeb2 上游 62 kb）也上调 Zeb2 启动子，提供了一系列保守的远端增强子的证据。删除一个超长程增强子拷贝所产生的表型表明该增强子在一个发育阶段的关键作用。 Zeb2 在这种发育背景下的单倍体不足反映了 MWS 的遗传，并且可能是这种人类遗传性疾病的一些性别依赖性、非神经特征的基础。
The zinc-finger, E-box-binding homeobox-2 (Zeb2) gene encodes a SMAD-interacting transcription factor that has diverse roles in development and disease. Mutations at the hZeb2 locus cause MowatWilson syndrome (MWS), a genetic disorder that is associated with mental retardation and other, case- and sex-dependent clinical features. Recent studies have detailed microRNA-mediated control of Zeb2, but little is known about the genomic context of this gene or of enhancer sequences that may direct its diverse functions. Here, we describe a novel transgenic rodent model in which Zeb2 regulatory sequence has been disrupted, resulting in a postnatal developmental phenotype that is autosomal dominant. The phenotype exhibits a genotype-by-sex interaction and manifests primarily as an acute attenuation of postnatal kidney development in males. Other aspects of embryonic and neonatal development, including neuronal, are unaffected. The transgene insertion site is associated with a 12 kb deletion, 1.2 Mb upstream of Zeb2, within a 4.1 Mb gene desert. A conserved sequence, derived from the deleted region, enhanced Zeb2 promoter activity in transcription assays. Tissue and temporal restriction of this enhancer activity may involve postnatal changes in proteins that bind this sequence. A control human/mouse VISTA enhancer (62 kb upstream of Zeb2) also up-regulated the Zeb2 promoter, providing evidence of a string of conserved distal enhancers. The phenotype arising from deletion of one copy of the extreme long-range enhancer indicates a critical role for this enhancer at one developmental stage. Haploinsufficiency of Zeb2 in this developmental context reflects inheritance of MWS and may underlie some sex-dependent, non-neural characteristics of this human inherited disorder.