Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air
Neuron-specific relaxation of Igf2r imprinting is associated with neuron-specific histone modifications and lack of its antisense transcript Air
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DOI：
10.1093/hmg/ddi255
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发表时间：
2005-09-01
影响因子：
3.5
通讯作者：
Kishino, T
中科院分区：
文献类型：
--
作者：
Yamasaki, Y;Kayashima, T;Kishino, T
小鼠胰岛素样生长因子II受体（Igf 2r）基因及其反义转录本Air在大多数组织中相互印记，但在大脑中，尽管有印记Air表达，但Igf 2r仍双等位基因表达。为了研究这种脑特异性放松的Igf2r印迹的分子机制，我们分析了其表达和表观遗传修饰的神经元，神经胶质细胞和成纤维细胞通过使用原代皮层细胞培养。在神经胶质细胞和成纤维细胞中，Igf2r是母系表达，Air是父系表达，而在原代培养的神经元中，Igf2r是双等位基因表达，Air不表达。在包括Air启动子的差异甲基化区域2（DMR 2）中，等位基因特异性DNA甲基化、差异H3和H4乙酰化以及H3K4和K9二甲基化在每种培养的细胞类型中得以维持。在DMR1中，包括Igf2r启动子，母源等位基因特异性DNA低甲基化，组蛋白H3和H4乙酰化和H3K4二甲基化在神经胶质细胞和成纤维细胞中是明显的。然而，在神经元中，检测到双等位基因DNA低甲基化和双等位基因组蛋白H3和H4乙酰化以及H3K4去甲基化。这些数据表明，大脑中缺乏Igf2r和Air的相互印记是由于与DMR 1中神经元特异性组蛋白修饰相关的Igf2r印记的神经元特异性松弛和Air表达的缺乏。我们观察到的双等位基因Igf2r的表达，没有空气表达的神经元揭示了空气的功能作为一个关键的效应器Igf2r沉默，并表明，神经元特异性表观遗传修饰相关的谱系确定的神经干细胞发挥关键作用，在控制印迹的反义转录。
The mouse insulin-like growth factor II receptor (Igf2r) gene and its antisense transcript Air are reciprocally imprinted in most tissues, but in the brain, Igf2r is biallelically expressed despite the imprinted Air expression. To investigate the molecular mechanisms of such brain-specific relaxation of Igf2r imprinting, we analyzed its expression and epigenetic modifications in neurons, glial cells and fibroblasts by the use of primary cortical cell cultures. In glial cells and fibroblasts, Igf2r was maternally expressed and Air was paternally expressed, whereas in the primary cultured neurons, Igf2r was biallelically expressed and Air was not expressed. In the differentially methylated region 2 (DMR2), which includes the Air promoter, allele-specific DNA methylation, differential H3 and H4 acetylation and H3K4 and K9 di-methylation were maintained in each cultured cell type. In DMR1, which includes the Igf2r promoter, maternal-allele-specific DNA hypomethylation, histones H3 and H4 acetylation and H3K4 di-methylation were apparent in glial cells and fibroblasts. However, in neurons, biallelic DNA hypomethylation and biallelic histones H3 and H4 acetylation and H3K4 di-methylation were detected. These data indicate that lack of reciprocal imprinting of Igf2r and Air in the brain results from neuron-specific relaxation of Igf2r imprinting associated with neuron-specific histone modifications in DMR1 and lack of Air expression. Our observation of biallelic Igf2r expression with no Air expression in neurons sheds light on the function of Air as a critical effector in Igf2r silencing and suggests that neuron-specific epigenetic modifications related to the lineage determination of neural stem cells play a critical role in controlling imprinting by antisense transcripts.