An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a.
An insulator loop resides between the synthetically interacting elements of the human/rat conserved breast cancer susceptibility locus MCS5A/Mcs5a.
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绝缘体环位于人/大鼠保守乳腺癌易感基因座 MCS5A/Mcs5a 的综合相互作用元件之间。
DOI：
10.1093/nar/gkr610
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发表时间：
2012
影响因子：
14.9
通讯作者：
Gould,Michael
中科院分区：
文献类型：
--
作者：
Smits,BartMG;Traun,BenjaminD;Devries,ThomasL;Tran,Ann;Samuelson,David;Haag,JillD;Gould,Michael
许多低表达率的乳腺癌易感基因位于非蛋白编码区，提示它们参与基因表达调控。我们鉴定了人/大鼠乳腺癌易感基因MCS 5A/Mcs 5a，该基因座通过免疫系统以非乳腺细胞自主的方式发挥作用。来自Wistar-Kyoto（WKy）大鼠品系的抗性Mcs 5a等位基因由两个非蛋白编码遗传元件组成，它们必须位于同一染色体上以引起表型。在这项研究中，我们发现了一个保守的高阶染色质结构inMCS 5A/Mcs 5alocated之间的合成相互作用的遗传元件。环状元件被示出为通过CTCF和粘附素结合。我们确定了T细胞中Fbxo 10表达的下调是一种强有力的候选机制，通过这种机制，耐药Mcs 5a等位基因的相互作用遗传元件调节乳腺癌易感性。最后，我们发现与乳腺癌风险相关的humanMCS 5A多态性位于环状结构的两侧，并在功能上相互作用以下调转录活性，类似于大鼠MCS 5A。我们提出了MCS 5a/Mcs 5ain的机制模型，其中CTCF介导的绝缘子环包含TOMM 5/Tomm 5基因，位于两者之间，并使合成和功能相互作用的抗性遗传变异体在物理上更接近。
Many low-penetrance breast cancer susceptibility loci are found to be located in non-protein-coding regions, suggesting their involvement in gene expression regulation. We identified the human/rat-conserved breast cancer susceptibility locusMCS5A/Mcs5a.This locus has been shown to act in a non-mammary cell-autonomous fashion through the immune system. The resistantMcs5aallele from the Wistar–Kyoto (WKy) rat strain consists of two non-protein-coding genetic elements that must be located on the same chromosome to elicit the phenotype. In this study, we show the presence of a conserved higher order chromatin structure inMCS5A/Mcs5alocated in between the synthetically interacting genetic elements. The looped elements are shown to be bound by CTCF and cohesin. We identify the downregulation ofFbxo10expression in T cells as a strong candidate mechanism through which the interacting genetic elements of the resistantMcs5aallele modulate mammary carcinoma susceptibility. Finally, we show that the humanMCS5Apolymorphisms associated with breast cancer risk are located at both sides of the looped structure and functionally interact to downregulate transcriptional activity, similar to ratMcs5a. We propose a mechanistic model forMCS5a/Mcs5ain which a CTCF-mediated insulator loop encompassing theTOMM5/Tomm5gene, resides in between and brings into closer physical proximity the synthetically and functionally interacting resistant genetic variants.