The imprinting box of the Prader-Willi/Angelman syndrome domain
The imprinting box of the Prader-Willi/Angelman syndrome domain
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DOI：
10.1038/82571
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发表时间：
2000-12-01
期刊：
影响因子：
30.8
通讯作者：
Razin, A
中科院分区：
文献类型：
--
作者：
Shemer, R;Hershko, AY;Razin, A
哺乳动物基因的一个子集以亲本来源的方式单等位地表达。这些基因受到印记过程的影响，在配子发生过程中根据其亲本来源表观遗传地标记等位基因。印记基因可以被组织成簇，例如人类染色体15 q11-q13上的2-Mb结构域和其在染色体7 c上的小鼠直向同源物（参考文献1）。父亲或母亲等位基因上的这一2-Mb结构域的缺失分别导致两种神经遗传性疾病，Prader-Willi综合征（PWS）或Angelman综合征（AS）。父本等位基因上的微缺失共享一个4.3 kb的短重叠区（SRO），其中包括SNRPN启动子/外显子1。引起PWS并沉默父系表达的基因（2）。母体等位基因上的微缺失共享位于SNRPN启动子上游35 kb的0.88-kb SRO（3），引起AS并减轻母体等位基因上基因的抑制（4）。在父系等位基因上携带AS和PWS缺失的个体显示PWS表型和基因型。这些观察结果表明，顺式元件内的AS-SRO和PWS-SRO构成一个印记盒，调节两条染色体上的整个域。在这里，我们表明，一个minitransgene组成的200 bp的SNRPN启动子/外显子1和1-kb的序列位于上游约35 kb的SNRPN启动子赋予印迹判断的差异甲基化，父母的起源特异性转录和异步复制。
A subset of mammalian genes is monoallelically expressed in a parent-of-origin manner. These genes are subject to an imprinting process that epigenetically marks alleles according to their parental origin during gametogenesis. Imprinted genes can be organized in clusters as exemplified by the 2-Mb domain on human chromosome 15q11-q13 and its mouse orthologue on chromosome 7c (ref. 1). Loss of this 2-Mb domain on the paternal or maternal allele results in two neurogenetic disorders, Prader-Willi syndrome (PWS) or Angelman syndrome (AS), respectively. Microdeletions on the paternal allele share a 4.3-kb short region of overlap (SRO), which includes the SNRPN promoter/exon1. cause PWS and silence paternally expressed genes(2). Microdeletions on the maternal allele share a 0.88-kb SRO located 35 kb upstream to the SNRPN promoter(3), cause AS and alleviate repression of genes on the maternal allele(4). Individuals carrying both AS and PWS deletions on the paternal allele show a PWS phenotype and genotype. These observations suggest that cis elements within the AS-SRO and PWS-SRO constitute an imprinting box that regulates the entire domain on both chromosomes. Here we show that a minitransgene composed of a 200-bp Snrpn promoter/exon1 and a 1-kb sequence located approximately 35 kb upstream to the SNRPN promoter confer imprinting as judged by differential methylation, parent-of-origin-specific transcription and asynchronous replication.