Human Molecular Genetics Advance Access originally published online on January 27, 2009
Human Molecular Genetics 2009 18(8):1424-1438; doi:10.1093/hmg/ddp049
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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
1 Department of Epigenetics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan 2 Mitsubishi Kagaku Institute of Life Science, 11 Minamiooya, Machida, Tokyo 194-8511, Japan 3 Center for Biological Resources and Informatics, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan 4 School of Health Sciences, Tokai University, Bohseidai, Isehara, Kanagawa 259-1193, Japan 5 Global Center of Excellence (GCOE) Program, International Research Center for Molecular Science in Tooth and Bone Diseases
* To whom correspondence should be addressed. Tel: +81 358034862; Fax: +81 358034863; Email: fishino.epgn{at}mri.tmd.ac.jp
Received November 27, 2008; Revised January 23, 2009; Accepted January 23, 2009
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 (+/
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 +/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 +/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.
Present address: Research Institute, International Medical Center of Japan, 1-2-21 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan.
Present address: IVF Namba Clinic, 1-17-28 Minamihorie, Nishi-ku, Osaka 550-0015, Japan.
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