The histone code regulating expression of the imprinted mouse Igf2r gene.
The histone code regulating expression of the imprinted mouse Igf2r gene.
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DOI：
10.1210/en.2003-0798
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发表时间：
2003-12
期刊：
影响因子：
4.8
通讯作者：
Youwen Yang;Tao Li;T. Vu;G. Ulaner;Ji-fan Hu;A. Hoffman
中科院分区：
文献类型：
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作者：
Youwen Yang;Tao Li;T. Vu;G. Ulaner;Ji-fan Hu;A. Hoffman
小鼠IGF-II受体（Igf 2 r）及其反义转录物Air在大多数正常组织中是双印迹的。已经假设了几种机制来解释Igf 2 r-Air印迹，包括由Air引起的Igf 2 r沉默，以及由两个差异甲基化区域（DMR 1和DMR 2）引起的Igf 2 r-Air的转录抑制。我们采用小家鼠×小家鼠种间小鼠和染色质免疫沉淀（ChIP）研究等位基因特异性组蛋白修饰的两个DMR。我们发现，在两个DMR中，Igf 2 r和Air的活性等位基因都与乙酰化组蛋白（H3和H4）、组蛋白H3的乙酰赖氨酸9（H3 K9-Ac）和组蛋白H3的甲基赖氨酸4（H3 K4-Me）相关。沉默的等位基因与甲基化DNA、去乙酰化H3 K9和未甲基化H3 K4相关。等位基因特异性组蛋白修饰存在于DMR 2中，DMR 2在配子中建立并代表Igf 2 r的DNA配子印记。在来自肝脏、肾脏和中枢神经系统组织的DMR 2中，H3 K9甲基化仅与沉默等位基因相关，而H3 S10磷酸化与活性等位基因相关。用5-氮杂-脱氧胞苷和/或曲古抑菌素A处理成纤维细胞导致沉默等位基因的部分再活化，这与双等位基因组蛋白乙酰化相关。在中枢神经系统中，尽管存在印迹Air转录物，但仍发生Igf 2 r的双等位基因表达。Igf 2 r印迹的组织特异性弛豫与Igf 2 r（DMR 1）启动子区的双等位基因组蛋白乙酰化和双等位基因H3 K4甲基化相关。我们提出了一个模型的组蛋白编码Igf 2 R，空气印迹，定义组蛋白修饰特定的假定配子印记DMR 2，并解释了组织特异性的小鼠的IGF 2 R印迹和IGF 2 R印迹在人类的情况下。
The mouse IGF-II receptor (Igf2r) and its antisense transcript Air are reciprocally imprinted in most normal tissues. Several mechanisms have been hypothesized to explain Igf2r-Air imprinting, including Igf2r silencing by Air, and transcriptional repression of Igf2r-Air by two differentially methylated regions (DMR1 and DMR2). We employed Mus musculus x Mus spretus interspecific mice and chromatin immunoprecipitation (ChIP) to investigate allele-specific histone modifications in the two DMRs. We show that, in both DMRs, the active alleles of both Igf2r, and Air are associated with acetylated histones (H3, and H4), acetyl lysine 9 of histone H3 (H3 K9-Ac), and methyl lysine 4 of histone H3 (H3 K4-Me). The silenced alleles are associated with methylated DNA, deacetylated H3 K9, and unmethylated H3 K4. Allele-specific histone modifications are present in the DMR2 that is established in the gametes and represents the DNA gametic-imprint of the Igf2r. In the DMR2 from liver, kidney, and central nervous system tissues, H3 K9 methylation is associated exclusively with the silenced allele, and H3 S10 phosphorylation with the active alleles. Treatment of fibroblast cells with 5-aza-deoxycytidine and/or Trichostatin A led to partial reactivation of the silenced allele, which correlates with biallelic histone acetylation. In central nervous system, despite the presence of imprinted Air transcripts, biallelic expression of Igf2r occurs. The tissue-specific relaxation of Igf2r imprinting correlates with biallelic histone acetylation, and biallelic H3 K4 methylation in the promoter region of Igf2r (DMR1). We propose a model of the histone code for Igf2r, and Air imprinting that defines histone modifications specific for the putative gametic imprint DMR2, and explains the tissue-specific imprinting of Igf2r in the mouse and the absence of IGF2R imprinting in human.