Terranova Rémi, Yokobayashi Shihori, Stadler Michael B, Otte Arie P, van Lohuizen Maarten, Orkin Stuart H, Peters Antoine H F M
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Dev Cell. 2008 Nov;15(5):668-79. doi: 10.1016/j.devcel.2008.08.015. Epub 2008 Oct 9.
Genomic imprinting regulates parental-specific expression of particular genes and is required for normal mammalian development. How imprinting is established during development is, however, largely unknown. To address this question, we studied the mouse Kcnq1 imprinted cluster at which paternal-specific silencing depends on expression of the noncoding RNA Kcnq1ot1. We show that Kcnq1ot1 is expressed from the zygote stage onward and rapidly associates with chromatin marked by Polycomb group (PcG) proteins and repressive histone modifications, forming a discrete repressive nuclear compartment devoid of RNA polymerase II, a configuration also observed at the Igf2r imprinted cluster. In this compartment, the paternal Kcnq1 cluster exists in a three-dimensionally contracted state. In vivo the PcG proteins Ezh2 and Rnf2 are independently required for genomic contraction and imprinted silencing. We propose that the formation of a parental-specific higher-order chromatin organization renders imprint clusters competent for monoallelic silencing and assign a central role to PcG proteins in this process.
基因组印记调控特定基因的亲本特异性表达，是正常哺乳动物发育所必需的。然而，印记在发育过程中是如何建立的，在很大程度上尚不清楚。为了解决这个问题，我们研究了小鼠Kcnq1印记簇，在该印记簇中，父本特异性沉默依赖于非编码RNA Kcnq1ot1的表达。我们发现，Kcnq1ot1从合子阶段开始表达，并迅速与由多梳蛋白家族（PcG）蛋白和抑制性组蛋白修饰标记的染色质结合，形成一个没有RNA聚合酶II的离散抑制性核区室，这种结构在Igf2r印记簇中也有观察到。在这个区室中，父本Kcnq1簇以三维收缩状态存在。在体内，PcG蛋白Ezh2和Rnf2独立地参与基因组收缩和印记沉默。我们提出，亲本特异性高阶染色质组织的形成使印记簇能够进行单等位基因沉默，并赋予PcG蛋白在此过程中的核心作用。
