Paternal deletion of Meg1/Grb10 DMR causes maternalization of the Meg1/Grb10 cluster in mouse proximal Chromosome 11 leading to severe pre- and postnatal growth retardation
Paternal deletion of Meg1/Grb10 DMR causes maternalization of the Meg1/Grb10 cluster in mouse proximal Chromosome 11 leading to severe pre- and postnatal growth retardation
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DOI：
10.1093/hmg/ddp049
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发表时间：
2009-04-15
影响因子：
3.5
通讯作者：
Ishino, Fumitoshi
中科院分区：
文献类型：
--
作者：
Shiura, Hirosuke;Nakamura, Kenji;Ishino, Fumitoshi
母体复制Meg1/Grb10所在的11号染色体近端（MatDp(prox11)）的小鼠表现出产前和产后生长迟缓。为了阐明导致生长异常的印迹基因，我们研究了该印迹区域的精确结构和调控机制，并通过删除Meg1/Grb10的差异甲基化区域（Meg1- dmr），生成了模拟MatDp（prox11）中观察到的印迹基因表达模式的新型模型小鼠。结果发现，Meg1/Grb10的邻近基因Cobl和Ddc也构成了印迹区。我们还发现，Meg1- dmr中由几个ctcf结合基序组成的小鼠特异性重复序列起到了沉默者的作用，这表明Meg1/Grb10印迹区采用了与H19/Igf2区域不同的调控机制。父本缺失Meg1-DMR （+/Delta DMR）导致母体表达的全身Meg1/Grb10型和卵泡Cobl上调，以及新生儿大脑和心脏中母体表达的Meg1/Grb10型和Ddc缺失，表明整个Meg1/Grb10印迹区域都母性化了。我们证实+/Delta DMR小鼠表现出与MatDp（prox11）小鼠相同的生长异常。胎儿和新生儿的生长对Meg1/Grb10 I型的表达水平非常敏感，表明Meg1/Grb10 I型的2倍增加是导致MatDp（prox11）和+/Delta DMR小鼠生长迟缓的主要原因之一。提示相应的人GRB10 I型在7p11-p13部分三体引起的银罗素综合征的病因学中起重要作用。
Mice with maternal duplication of proximal Chromosome 11 (MatDp(prox11)), where Meg1/Grb10 is located, exhibit pre- and postnatal growth retardation. To elucidate the responsible imprinted gene for the growth abnormality, we examined the precise structure and regulatory mechanism of this imprinted region and generated novel model mice mimicking the pattern of imprinted gene expression observed in the MatDp(prox11) by deleting differentially methylated region of Meg1/Grb10 (Meg1-DMR). It was found that Cobl and Ddc, the neighboring genes of Meg1/Grb10, also comprise the imprinted region. We also found that the mouse-specific repeat sequence consisting of several CTCF-binding motifs in the Meg1-DMR functions as a silencer, suggesting that the Meg1/Grb10 imprinted region adopted a different regulatory mechanism from the H19/Igf2 region. Paternal deletion of the Meg1-DMR (+/Delta DMR) caused both upregulation of the maternally expressed Meg1/Grb10 Type I in the whole body and Cobl in the yolk sac and loss of paternally expressed Meg1/Grb10 Type II and Ddc in the neonatal brain and heart, respectively, demonstrating maternalization of the entire Meg1/Grb10 imprinted region. We confirmed that the +/Delta DMR mice exhibited the same growth abnormalities as the MatDp(prox11) mice. Fetal and neonatal growth was very sensitive to the expression level of Meg1/Grb10 Type I, indicating that the 2-fold increment of the Meg1/Grb10 Type I is one of the major causes of the growth retardation observed in the MatDp(prox11) and +/Delta DMR mice. This suggests that the corresponding human GRB10 Type I plays an important role in the etiology of Silver-Russell syndrome caused by partial trisomy of 7p11-p13.