Two distinct mechanisms of silencing by the KvDMR1 imprinting control region
Two distinct mechanisms of silencing by the KvDMR1 imprinting control region
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DOI：
10.1038/sj.emboj.7601960
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发表时间：
2008-01-09
期刊：
影响因子：
11.4
通讯作者：
Higgins, Michael J.
中科院分区：
文献类型：
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作者：
Shin, Jong-Yeon;Fitzpatrick, Galina V.;Higgins, Michael J.
众所周知，印迹控制区（ICRs）通过两种机制之一来抑制基因，ctcf介导的绝缘或非编码rna （ncRNAs）的转录。KvDMR1 ICR既包含kcnq10t1 ncRNA的启动子，也包含位于增强子阻断试验中显示抑制活性序列中的两个ctcf结合位点。KvDMR1的缺失导致7号染色体远端普遍存在8个母体特异性基因的双等位基因表达。在这里，我们报道，虽然kcnqot1转录物的截断会导致胎盘中这些基因的印迹表达缺失，但它不会影响胚胎组织中Cdkn1c的印迹表达，尽管Cdkn1c的父本特异性甲基化普遍缺失。与组织特异性印迹表达缺失一致的是，这些突变小鼠的生长缺陷没有先前在KvDMR1缺失小鼠中观察到的严重。这项研究表明，KvDMR1位点可以通过独立于kcnqot1转录的机制沉默Cdkn1c，可能是通过ctcf相关的抑制，使其成为能够通过两种不同机制沉默同一基因的ICR的第一个例子。
Imprinting control regions (ICRs) are known to repress genes by utilizing one of two mechanisms, CTCF-mediated insulation or the transcription of non-coding RNAs (ncRNAs). The KvDMR1 ICR contains both the promoter for the Kcnq1ot1 ncRNA and two CTCF-binding sites located within sequences exhibiting repressive activity in enhancer-blocking assays. Deletion of KvDMR1 results in ubiquitous biallelic expression of eight maternal-specific genes in distal chromosome 7. Here we report that while truncation of the Kcnq1ot1 transcript results in the loss of imprinted expression of these genes in the placenta, it does not affect imprinted expression of Cdkn1c in a subset of embryonic tissues despite universal loss of paternal-specific methylation at Cdkn1c. Consistent with tissue-specific loss of imprinted expression, growth deficiency of these mutant mice was less severe than that observed previously in mice with deletion of KvDMR1. This study demonstrates that the KvDMR1 locus can silence Cdkn1c by a mechanism independent of Kcnq1ot1 transcription, perhaps by CTCF-associated repression, making it the first example of an ICR capable of silencing the same gene by two distinct mechanisms.