The two-domain hypothesis in Beckwith-Wiedemann syndrome: autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster
The two-domain hypothesis in Beckwith-Wiedemann syndrome: autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster
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DOI：
10.1093/hmg/ddi047
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发表时间：
2005-02-15
影响因子：
3.5
通讯作者：
Riccio, A
中科院分区：
文献类型：
--
作者：
Cerrato, F;Sparago, A;Riccio, A
一个大的印迹基因簇位于小鼠远端7号染色体上。该簇在人类中是很保守的，其失调导致过度生长和肿瘤相关的Beckwith-Wiedemann综合征。两个印记中心（IC 1和IC 2）控制不同的基因组已被确定在集群中，提出的假设，集群分为两个功能独立的域。然而，在IC 2域（如Cdkn 1c和Kcnq 1）的基因印迹的调节机制还没有得到很好的定义，最近的证据表明，位于遥远的顺式作用元件所需的IC 2印迹。我们表明，在IC 2和IC 2域的5个基因的印记表达的母系生殖系甲基化是正确的复制在800 kb的YAC转基因时，转移到其正常的染色体背景之外。这些结果，加上以前的转基因研究，定位关键的印迹控制元件内的400 kb区域的IC 2的着丝粒，并证明，每个集群的两个域包含的顺式作用元件所需的印迹控制自己的基因。最后，母亲，但不是父亲，转基因的传输结果在胎儿生长限制，这表明在进化过程中的收购印迹可能已经促进了胚胎生长的两个领域的相反效果。
A large cluster of imprinted genes is located on the mouse distal chromosome 7. This cluster is well conserved in humans and its dysregulation results in the overgrowth- and tumour-associated Beckwith-Wiedemann syndrome. Two imprinting centres (IC1 and IC2) controlling different sets of genes have been identified in the cluster, raising the hypothesis that the cluster is divided into two functionally independent domains. However, the mechanisms by which imprinting of genes in the IC2 domain (e.g. Cdkn1c and Kcnq1) is regulated have not been well defined, and recent evidence indicates that distantly located cis-acting elements are required for IC2 imprinting. We show that the maternal germ-line methylation at IC2 and the imprinted expression of five genes of the IC2 domain are correctly reproduced on an 800 kb YAC transgene when transferred outside of their normal chromosomal context. These results, together with previous transgenic studies, locate key imprinting control elements within a 400 kb region centromeric of IC2 and demonstrate that each of the two domains of the cluster contains the cis-acting elements required for the imprinting control of its own genes. Finally, maternal, but not paternal, transmission of the transgene results in fetal growth restriction, suggesting that during evolution the acquisition of imprinting may have been facilitated by the opposite effects of the two domains on embryo growth.