Cleary M A, van Raamsdonk C D, Levorse J, Zheng B, Bradley A, Tilghman S M
Howard Hughes Medical Institute and Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Nat Genet. 2001 Sep;29(1):78-82. doi: 10.1038/ng715.
Genomic imprinting is an epigenetic process in which the activity of a gene is determined by its parent of origin. Mechanisms governing genomic imprinting are just beginning to be understood. However, the tendency of imprinted genes to exist in chromosomal clusters suggests a sharing of regulatory elements. To better understand imprinted gene clustering, we disrupted a cluster of imprinted genes on mouse distal chromosome 7 using the Cre/loxP recombination system. In mice carrying a site-specific translocation separating Cdkn1c and Kcnq1, imprinting of the genes retained on chromosome 7, including Kcnq1, Kcnq1ot1, Ascl2, H19 and Igf2, is unaffected, demonstrating that these genes are not regulated by elements near or telomeric to Cdkn1c. In contrast, expression and imprinting of the translocated Cdkn1c, Slc22a1l and Tssc3 on chromosome 11 are affected, consistent with the hypothesis that elements regulating both expression and imprinting of these genes lie within or proximal to Kcnq1. These data support the proposal that chromosomal abnormalities, including translocations, within KCNQ1 that are associated with the human disease Beckwith-Wiedemann syndrome (BWS) may disrupt CDKN1C expression. These results underscore the importance of gene clustering for the proper regulation of imprinted genes.
基因组印记是一种表观遗传过程，其中基因的活性由其起源亲本决定。控制基因组印记的机制才刚刚开始被理解。然而，印记基因倾向于存在于染色体簇中，这表明调控元件是共享的。为了更好地理解印记基因的聚类，我们使用Cre/loxP重组系统破坏了小鼠7号远端染色体上的一组印记基因。在携带位点特异性易位从而分离Cdkn1c和Kcnq1的小鼠中，保留在7号染色体上的基因（包括Kcnq1、Kcnq1ot1、Ascl2、H19和Igf2）的印记不受影响，这表明这些基因不受Cdkn1c附近或端粒区域元件的调控。相反，11号染色体上易位的Cdkn1c、Slc22a1l和Tssc3的表达和印记受到影响，这与以下假设一致：调控这些基因表达和印记的元件位于Kcnq1内部或近端。这些数据支持了这样的提议：与人类疾病贝克威思-维德曼综合征（BWS）相关的KCNQ1内的染色体异常（包括易位）可能会破坏CDKN1C的表达。这些结果强调了基因聚类对于印记基因正确调控的重要性。
