H19 and Igf2 monoallelic expression is regulated in two distinct ways by a shared cis acting regulatory region upstream of H19.
H19 and Igf2 monoallelic expression is regulated in two distinct ways by a shared cis acting regulatory region upstream of H19.
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DOI：
10.1101/gad.14.10.1186
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发表时间：
2000-05
影响因子：
10.5
通讯作者：
M. Srivastava;Sandra Hsieh;Alexander Grinberg;Lisa Williams-Simons;S. Huang;Karl Pfeifer
中科院分区：
文献类型：
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作者：
M. Srivastava;Sandra Hsieh;Alexander Grinberg;Lisa Williams-Simons;S. Huang;Karl Pfeifer
H19和Igf2分别以单等位基因的方式从母体和父亲染色体中表达。H19上游的一个区域已被证明以顺式方式调节这两个基因的印迹表达。我们利用基于loxP/cre重组酶的策略在小鼠中有条件地删除该区域，以确定上游区域在启动和维持H19和Igf2的印迹表达时的时间要求。对H19和Igf2等位基因特异性表达和H19启动子DNA甲基化的分析表明，该区域以不同的方式控制这两个基因的单等位基因表达，表明它含有两种功能不同的调控元件。根据Igf2作为绝缘体的建议作用，需要该区域的继续存在来抑制母体Igf2。然而，它在保持父本H19启动子沉默方面没有直接作用。相反，在父本染色体上，上游元件在发育过程中介导H19启动子区域的表观遗传修饰，导致H19的转录沉默。此后，它的存在对于防止转录是多余的。目前，沉默元件的这种时间要求似乎是哺乳动物系统中独特的顺式活动。然而，其他的顺式作用元件，无论是正的还是负的，很可能具有影响染色质结构稳定变化的能力，并且不需要不断地向转录机制发出信号。
H19 and Igf2 are expressed in a monoallelic fashion from the maternal and paternal chromosomes, respectively. A region upstream of H19 has been shown to regulate such imprinted expression of both genes in cis. We have taken advantage of a loxP/cre recombinase-based strategy to delete this region in mice in a conditional manner to determine the temporal requirement of the upstream region in initiating and maintaining the imprinted expression of H19 and Igf2. Analysis of allele-specific expression of H19 and Igf2 and DNA methylation at the H19 promoter demonstrates that this region controls the monoallelic expression of the two genes in different ways, suggesting that it harbors two functionally distinct regulatory elements. Continued presence of the region is required to silence maternal Igf2 in accordance with its proposed role as an insulator. However, it does not have a direct role in keeping the paternal H19 promoter silenced. Instead, on the paternal chromosome, the upstream element mediates epigenetic modifications of the H19 promoter region during development, leading to transcriptional silencing of H19. Thereafter, its presence is redundant for preventing transcription. Presently, this temporal requirement of the silencing element appears to be a unique cis activity in the mammalian system. However, it is likely that other cis-acting elements, positive and negative, have the ability to effect stable changes in the chromatin structure and are not constantly required to give signals to the transcriptional machinery.